Topic: Basic Research

Abstract

PLX3397, a CSF1 receptor inhibitor, limits allotransplantation-induced vascular remodelling.

Almonte VM, Uriyanghai U, Egaña-Gorroño L, Parikh D, ... Riascos-Bernal DF, Sibinga NES
Aims
Graft vascular disease (GVD), a clinically important and highly complex vascular occlusive disease, arises from the interplay of multiple cellular and molecular pathways. While occlusive intimal lesions are composed predominantly of smooth-muscle-like cells (SMLCs), the origin of these cells and the stimuli leading to their accumulation in GVD are uncertain. Macrophages have recently been identified as both potential drivers of intimal hyperplasia and precursors that undergo transdifferentiation to become SMLCs in non-transplant settings. Colony-stimulating factor-1 (CSF1) is a well-known regulator of macrophage development and differentiation, and prior preclinical studies have shown that lack of CSF1 limits GVD. We sought to identify the origins of SMLCs and of cells expressing the CSF1 receptor (CSF1R) in GVD, and to test the hypothesis that pharmacologic inhibition of CSF1 signalling would curtail both macrophage and SMLC activities and decrease vascular occlusion.
Methods and results
We used genetically modified mice and a vascular transplant model with minor antigen mismatch to assess cell origins. We found that neointimal SMLCs derive from both donor and recipient, and that transdifferentiation of macrophages to SMLC phenotype is minimal in this model. Cells expressing CSF1R in grafts were identified as recipient-derived myeloid cells of Cx3cr1 lineage, and these cells rarely expressed smooth muscle marker proteins. Blockade of CSF1R activity using the tyrosine kinase inhibitor PLX3397 limited the expression of genes associated with innate immunity and decreased levels of circulating monocytes and intimal macrophages. Importantly, PLX3397 attenuated the development of GVD in arterial allografts.
Conclusion
These studies provide proof of concept for pharmacologic inhibition of the CSF1/CSF1R signalling pathway as a therapeutic strategy in GVD. Further preclinical testing of this pathway in GVD is warranted.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Sep 2022; 118:2718-2731
Almonte VM, Uriyanghai U, Egaña-Gorroño L, Parikh D, ... Riascos-Bernal DF, Sibinga NES
Cardiovasc Res: 20 Sep 2022; 118:2718-2731 | PMID: 34478521
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Abstract

Role of PDE10A in vascular smooth muscle cell hyperplasia and pathological vascular remodelling.

Luo L, Cai Y, Zhang Y, Hsu CG, ... Berk BC, Yan C
Aims
Intimal hyperplasia is a common feature of vascular remodelling disorders. Accumulation of synthetic smooth muscle cell (SMC)-like cells is the main underlying cause. Current therapeutic approaches including drug-eluting stents are not perfect due to the toxicity on endothelial cells and novel therapeutic strategies are needed. Our preliminary screening for dysregulated cyclic nucleotide phosphodiesterases (PDEs) in growing SMCs revealed the alteration of PDE10A expression. Herein, we investigated the function of PDE10A in SMC proliferation and intimal hyperplasia both in vitro and in vivo.
Methods and results
RT-qPCR, immunoblot, and in situ proximity ligation assay were performed to determine PDE10A expression in synthetic SMCs and injured vessels. We found that PDE10A mRNA and/or protein levels are up-regulated in cultured SMCs upon growth stimulation, as well as in intimal cells in injured mouse femoral arteries. To determine the cellular functions of PDE10A, we focused on its role in SMC proliferation. The anti-mitogenic effects of PDE10A on SMCs were evaluated via cell counting, BrdU incorporation, and flow cytometry. We found that PDE10A deficiency or inhibition arrested the SMC cell cycle at G1-phase with a reduction of cyclin D1. The anti-mitotic effect of PDE10A inhibition was dependent on cGMP-dependent protein kinase Iα (PKGIα), involving C-natriuretic peptide (CNP) and particulate guanylate cyclase natriuretic peptide receptor 2 (NPR2). In addition, the effects of genetic depletion and pharmacological inhibition of PDE10A on neointimal formation were examined in a mouse model of femoral artery wire injury. Both PDE10A knockout and inhibition decreased injury-induced intimal thickening in femoral arteries by at least 50%. Moreover, PDE10A inhibition decreased ex vivo remodelling of cultured human saphenous vein segments.
Conclusions
Our findings indicate that PDE10A contributes to SMC proliferation and intimal hyperplasia at least partially via antagonizing CNP/NPR2/cGMP/PKG1α signalling and suggest that PDE10A may be a novel drug target for treating vascular occlusive disease.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Sep 2022; 118:2703-2717
Luo L, Cai Y, Zhang Y, Hsu CG, ... Berk BC, Yan C
Cardiovasc Res: 20 Sep 2022; 118:2703-2717 | PMID: 34550322
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Abstract

Circadian rhythms in ischaemic heart disease: key aspects for preclinical and translational research: position paper of the ESC working group on cellular biology of the heart.

Lecour S, Du Pré BC, Bøtker HE, Brundel BJJM, ... Young ME, Van Laake LW
Circadian rhythms are internal regulatory processes controlled by molecular clocks present in essentially every mammalian organ that temporally regulate major physiological functions. In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility, and coagulation. Recent experimental and clinical studies highlight the possible importance of circadian rhythms in the pathophysiology, outcome, or treatment success of cardiovascular disease, including ischaemic heart disease. Disturbances in circadian rhythms are associated with increased cardiovascular risk and worsen outcome. Therefore, it is important to consider circadian rhythms as a key research parameter to better understand cardiac physiology/pathology, and to improve the chances of translation and efficacy of cardiac therapies, including those for ischaemic heart disease. The aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to highlight key aspects of circadian rhythms to consider for improvement of preclinical and translational studies related to ischaemic heart disease and cardioprotection. Applying these considerations to future studies may increase the potential for better translation of new treatments into successful clinical outcomes.

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Cardiovasc Res: 20 Sep 2022; 118:2566-2581
Lecour S, Du Pré BC, Bøtker HE, Brundel BJJM, ... Young ME, Van Laake LW
Cardiovasc Res: 20 Sep 2022; 118:2566-2581 | PMID: 34505881
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Abstract

Pharmacological inhibition of adipose tissue adipose triglyceride lipase by Atglistatin prevents catecholamine-induced myocardial damage.

Thiele A, Luettges K, Ritter D, Beyhoff N, ... Kintscher U, Foryst-Ludwig A
Aims
Heart failure (HF) is characterized by an overactivation of β-adrenergic signalling that directly contributes to impairment of myocardial function. Moreover, β-adrenergic overactivation induces adipose tissue lipolysis, which may further worsen the development of HF. Recently, we demonstrated that adipose tissue-specific deletion of adipose triglyceride lipase (ATGL) prevents pressure-mediated HF in mice. In this study, we investigated the cardioprotective effects of a new pharmacological inhibitor of ATGL, Atglistatin, predominantly targeting ATGL in adipose tissue, on catecholamine-induced cardiac damage.
Methods and results
Male 129/Sv mice received repeated injections of isoproterenol (ISO, 25 mg/kg BW) to induce cardiac damage. Five days prior to ISO application, oral Atglistatin (2 mmol/kg diet) or control treatment was started. Two and twelve days after the last ISO injection cardiac function was analysed by echocardiography. The myocardial deformation was evaluated using speckle-tracking-technique. Twelve days after the last ISO injection, echocardiographic analysis revealed a markedly impaired global longitudinal strain, which was significantly improved by the application of Atglistatin. No changes in ejection fraction were observed. Further studies included histological-, WB-, and RT-qPCR-based analysis of cardiac tissue, followed by cell culture experiments and mass spectrometry-based lipidome analysis. ISO application induced subendocardial fibrosis and a profound pro-apoptotic cardiac response, as demonstrated using an apoptosis-specific gene expression-array. Atglistatin treatment led to a dramatic reduction of these pro-fibrotic and pro-apoptotic processes. We then identified a specific set of fatty acids (FAs) liberated from adipocytes under ISO stimulation (palmitic acid, palmitoleic acid, and oleic acid), which induced pro-apoptotic effects in cardiomyocytes. Atglistatin significantly blocked this adipocytic FA secretion.
Conclusion
This study demonstrates cardioprotective effects of Atglistatin in a mouse model of catecholamine-induced cardiac damage/dysfunction, involving anti-apoptotic and anti-fibrotic actions. Notably, beneficial cardioprotective effects of Atglistatin are likely mediated by non-cardiac actions, supporting the concept that pharmacological targeting of adipose tissue may provide an effective way to treat cardiac dysfunction.

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Cardiovasc Res: 24 Aug 2022; 118:2488-2505
Thiele A, Luettges K, Ritter D, Beyhoff N, ... Kintscher U, Foryst-Ludwig A
Cardiovasc Res: 24 Aug 2022; 118:2488-2505 | PMID: 34061169
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Abstract

Impairment of mitophagy and autophagy accompanies calcific aortic valve stenosis favouring cell death and the severity of disease.

Morciano G, Patergnani S, Pedriali G, Cimaglia P, ... Ferrari R, Pinton P
Aims
In the last 15 years, some observations tried to shed light on the dysregulation of the cellular self-digestion process in calcific aortic valve stenosis (CAVS), but the results obtained remain still controversial. This work is aimed to definitively establish the trend of autophagy in patients affected by CAVS, to analyse the putative involvement of other determinants, which impact on the mitochondrial quality control mechanisms and to explore possible avenues for pharmacological interventions in the treatment of CAVS.
Methods and results
This observational study, performed exclusively in ex vivo human samples (cells and serum), by using biochemical approaches and correlations with clinical data, describes new biological features of the calcified valve in terms of mitochondrial dysfunctions. In detail, we unveiled a significant deficiency in mitochondrial respiration and in ATP production coupled to increase production of lactates. In addition, mitochondrial population in the pathologic group is aged with significant alterations in biogenesis and mitophagy pathways. We are also reporting an updated view about autophagy accompanying the calcification process and advanced stages of the disease. We provided evidence for a rapamycin-based therapeutic strategy to revert the calcified phenotype to the wild type one.
Conclusion
Our data suggest that the CAVS phenotype is featured by defects in mitochondrial quality control mechanisms and that autophagy is not activated enough to counteract cell death and sustain cell functions. Thus, boosting autophagy and mitophagy from short- to long-term reverts quite all pathological phenotypes.

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Cardiovasc Res: 24 Aug 2022; 118:2548-2559
Morciano G, Patergnani S, Pedriali G, Cimaglia P, ... Ferrari R, Pinton P
Cardiovasc Res: 24 Aug 2022; 118:2548-2559 | PMID: 34375401
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Abstract

Recommendations for nomenclature and definition of cell products intended for human cardiovascular use.

Taylor DA, Chacon-Alberty L, Sampaio LC, Hierro MGD, ... Bolli R, Cardiovascular Cell Therapy Research Network (CCTRN)
Exogenous cell-based therapy has emerged as a promising new strategy to facilitate repair of hearts damaged by acute or chronic injury. However, the field of cell-based therapy is handicapped by the lack of standardized definitions and terminology, making comparisons across studies challenging. Even the term \'stem cell therapy\' is misleading because only a small percentage of cells derived from adult bone marrow, peripheral blood, or adipose tissue meets the accepted haematopoietic or developmental definition of stem cells. Furthermore, cells (stem or otherwise) are dynamic biological products, meaning that their surface-marker expression, phenotypic and functional characteristics, and the products they secrete in response to their microenvironment can change. It is also important to point out that most surface markers are seldom specific for a cell type. In this article, we discuss the lack of consistency in the descriptive terminology used in cell-based therapies and offer guidelines aimed at standardizing nomenclature and definitions to improve communication among investigators and the general public.

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Cardiovasc Res: 24 Aug 2022; 118:2428-2436
Taylor DA, Chacon-Alberty L, Sampaio LC, Hierro MGD, ... Bolli R, Cardiovascular Cell Therapy Research Network (CCTRN)
Cardiovasc Res: 24 Aug 2022; 118:2428-2436 | PMID: 34387303
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Abstract

Lymphatic contractile function: a comprehensive review of drug effects and potential clinical application.

Russell PS, Hong J, Trevaskis NL, Windsor JA, Martin ND, Phillips ARJ
The lymphatic system and the cardiovascular (CV) system work together to maintain body fluid homeostasis. Despite that, the lymphatic system has been relatively neglected as a potential drug target and a source of adverse effects from CV drugs. Like the heart, the lymphatic vessels undergo phasic contractions to promote lymph flow against a pressure gradient. Dysfunction or failure of the lymphatic pump results in fluid imbalance and tissue oedema. While this can be due to drug effects, it is also a feature of breast cancer-associated lymphoedema, chronic venous insufficiency, congestive heart failure, and acute systemic inflammation. There are currently no specific drug treatments for lymphatic pump dysfunction in clinical use despite the wealth of data from pre-clinical studies. The aim of this study was to identify (i) drugs with direct effects on lymphatic tonic and phasic contractions with potential for clinical application, and (ii) drugs in current clinical use that have a positive or negative side effect on lymphatic function. We comprehensively reviewed all studies that tested the direct effect of a drug on the contractile function of lymphatic vessels. Of the 208 drugs identified from 193 studies, about a quarter had only stimulatory effects on lymphatic tone, contraction frequency, and/or contraction amplitude. Of Food and Drug Administration-approved drugs, there were 14 that increased lymphatic phasic contractile function. The most frequently used class of drugs with inhibitory effects on lymphatic pump function were the calcium channels blockers. This review highlights the opportunity for specific drug treatments of lymphatic dysfunction in various disease states and for avoiding adverse drug effects on lymphatic contractile function.

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Cardiovasc Res: 24 Aug 2022; 118:2437-2457
Russell PS, Hong J, Trevaskis NL, Windsor JA, Martin ND, Phillips ARJ
Cardiovasc Res: 24 Aug 2022; 118:2437-2457 | PMID: 34415332
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Abstract

Single-cell RNA sequencing profiling of mouse endothelial cells in response to pulmonary arterial hypertension.

Rodor J, Chen SH, Scanlon JP, Monteiro JP, ... Brittan M, Baker AH
Aims
Endothelial cell (EC) dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension (PAH). We aimed to characterize EC dynamics in PAH at single-cell resolution.
Methods and results
We carried out single-cell RNA sequencing (scRNA-seq) of lung ECs isolated from an EC lineage-tracing mouse model in Control and SU5416/hypoxia-induced PAH conditions. EC populations corresponding to distinct lung vessel types, including two discrete capillary populations, were identified in both Control and PAH mice. Differential gene expression analysis revealed global PAH-induced EC changes that were confirmed by bulk RNA-seq. This included upregulation of the major histocompatibility complex class II pathway, supporting a role for ECs in the inflammatory response in PAH. We also identified a PAH response specific to the second capillary EC population including upregulation of genes involved in cell death, cell motility, and angiogenesis. Interestingly, four genes with genetic variants associated with PAH were dysregulated in mouse ECs in PAH. To compare relevance across PAH models and species, we performed a detailed analysis of EC heterogeneity and response to PAH in rats and humans through whole-lung PAH scRNA-seq datasets, revealing that 51% of up-regulated mouse genes were also up-regulated in rat or human PAH. We identified promising new candidates to target endothelial dysfunction including CD74, the knockdown of which regulates EC proliferation and barrier integrity in vitro. Finally, with an in silico cell ordering approach, we identified zonation-dependent changes across the arteriovenous axis in mouse PAH and showed upregulation of the Serine/threonine-protein kinase Sgk1 at the junction between the macro- and microvasculature.
Conclusion
This study uncovers PAH-induced EC transcriptomic changes at a high resolution, revealing novel targets for potential therapeutic candidate development.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 24 Aug 2022; 118:2519-2534
Rodor J, Chen SH, Scanlon JP, Monteiro JP, ... Brittan M, Baker AH
Cardiovasc Res: 24 Aug 2022; 118:2519-2534 | PMID: 34528097
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Abstract

Endothelial Poldip2 regulates sepsis-induced lung injury via Rho pathway activation.

Dolmatova EV, Forrester SJ, Wang K, Ou Z, ... Hernandes MS, Griendling KK
Aims
Sepsis-induced lung injury is associated with significant morbidity and mortality. Previously, we showed that heterozygous deletion of polymerase δ-interacting protein 2 (Poldip2) was protective against sepsis-induced lung injury. Since endothelial barrier disruption is thought to be the main mechanism of sepsis-induced lung injury, we sought to determine if the observed protection was specifically due to the effect of reduced endothelial Poldip2.
Methods and results
Endothelial-specific Poldip2 knock-out mice (EC-/-) and their wild-type littermates (EC+/+) were injected with saline or lipopolysaccharide (18 mg/kg) to model sepsis-induced lung injury. At 18 h post-injection mice, were euthanized and bronchoalveolar lavage (BAL) fluid and lung tissue were collected to assess leucocyte infiltration. Poldip2 EC-/- mice showed reduced lung leucocyte infiltration in BAL (0.21 ± 0.9×106 vs. 1.29 ± 1.8×106 cells/mL) and lung tissue (12.7 ± 1.8 vs. 23 ± 3.7% neutrophils of total number of cells) compared to Poldip2 EC+/+ mice. qPCR analysis of the lung tissue revealed a significantly dampened induction of inflammatory gene expression (TNFα 2.23 ± 0.39 vs. 4.15 ± 0.5-fold, IκBα 4.32 ± 1.53 vs. 8.97 ± 1.59-fold), neutrophil chemoattractant gene expression (CXCL1 68.8 ± 29.6 vs. 147 ± 25.7-fold, CXCL2 65 ± 25.6 vs. 215 ± 27.3-fold) and a marker of endothelial activation (VCAM1 1.25 ± 0.25 vs. 3.8 ± 0.38-fold) in Poldip2 EC-/- compared to Poldip2 EC+/+ lungs. An in vitro model using human pulmonary microvascular endothelial cells was used to assess the effect of Poldip2 knock-down on endothelial activation and permeability. TNFα-induced endothelial permeability and VE-cadherin disruption were significantly reduced with siRNA-mediated knock-down of Poldip2 (5 ± 0.5 vs. 17.5 ± 3-fold for permeability, 1.5 ± 0.4 vs. 10.9 ± 1.3-fold for proportion of disrupted VE-cadherin). Poldip2 knock-down altered expression of Rho-GTPase-related genes, which correlated with reduced RhoA activation by TNFα (0.94 ± 0.05 vs. 1.29 ± 0.01 of relative RhoA activity) accompanied by redistribution of active-RhoA staining to the centre of the cell.
Conclusion
Poldip2 is a potent regulator of endothelial dysfunction during sepsis-induced lung injury, and its endothelium-specific inhibition may provide clinical benefit.

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Cardiovasc Res: 24 Aug 2022; 118:2506-2518
Dolmatova EV, Forrester SJ, Wang K, Ou Z, ... Hernandes MS, Griendling KK
Cardiovasc Res: 24 Aug 2022; 118:2506-2518 | PMID: 34528082
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Abstract

Vascular endothelial tissue factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis.

Witkowski M, Witkowski M, Friebel J, Buffa JA, ... Rauch U, Hazen SL
Aims
Gut microbiota and their generated metabolites impact the host vascular phenotype. The metaorganismal metabolite trimethylamine N-oxide (TMAO) is both associated with adverse clinical thromboembolic events, and enhances platelet responsiveness in subjects. The impact of TMAO on vascular Tissue Factor (TF) in vivo is unknown. Here, we explore whether TMAO-enhanced thrombosis potential extends beyond TMAO effects on platelets, and is linked to TF. We also further explore the links between gut microbiota and vascular endothelial TF expression in vivo.
Methods and results
In initial exploratory clinical studies, we observed that among sequential stable subjects (n = 2989) on anti-platelet therapy undergoing elective diagnostic cardiovascular evaluation at a single-site referral centre, TMAO levels were associated with an increased incident (3 years) risk for major adverse cardiovascular events (MACE) (myocardial infarction, stroke, or death) [4th quartile (Q4) vs. Q1 adjusted hazard ratio (HR) 95% confidence interval (95% CI), 1.73 (1.25-2.38)]. Similar results were observed within subjects on aspirin mono-therapy during follow-up [adjusted HR (95% CI) 1.75 (1.25-2.44), n = 2793]. Leveraging access to a second higher risk cohort with previously reported TMAO data and monitoring of anti-platelet medication use, we also observed a strong association between TMAO and incident (1 year) MACE risk in the multi-site Swiss Acute Coronary Syndromes Cohort, focusing on the subset (n = 1469) on chronic dual anti-platelet therapy during follow-up [adjusted HR (95% CI) 1.70 (1.08-2.69)]. These collective clinical data suggest that the thrombosis-associated effects of TMAO may be mediated by cells/factors that are not inhibited by anti-platelet therapy. To test this, we first observed in human microvascular endothelial cells that TMAO dose-dependently induced expression of TF and vascular cell adhesion molecule (VCAM)1. In mouse studies, we observed that TMAO-enhanced aortic TF and VCAM1 mRNA and protein expression, which upon immunolocalization studies, was shown to co-localize with vascular endothelial cells. Finally, in arterial injury mouse models, TMAO-dependent enhancement of in vivo TF expression and thrombogenicity were abrogated by either a TF-inhibitory antibody or a mechanism-based microbial choline TMA-lyase inhibitor (fluoromethylcholine).
Conclusion
Endothelial TF contributes to TMAO-related arterial thrombosis potential, and can be specifically blocked by targeted non-lethal inhibition of gut microbial choline TMA-lyase.

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Cardiovasc Res: 27 Jul 2022; 118:2367-2384
Witkowski M, Witkowski M, Friebel J, Buffa JA, ... Rauch U, Hazen SL
Cardiovasc Res: 27 Jul 2022; 118:2367-2384 | PMID: 34352109
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Abstract

Cardiovascular effects of non-insulin glucose-lowering agents: a comprehensive review of trial evidence and potential cardioprotective mechanisms.

Savarese G, Butler J, Lund LH, Bhatt DL, Anker SD
Type 2 diabetes mellitus (T2DM) is highly prevalent and associated with a two-fold increased mortality, mostly explained by cardiovascular diseases. Trial evidence on older glucose-lowering agents such as metformin and sulfonylureas is limited in terms of cardiovascular efficacy. Since 2008, after rosiglitazone was observed to increase the risk of myocardial infarction and heart failure (HF), cardiovascular outcome trials (CVOTs) have been required by regulators for licensing new glucose-lowering agents. In the following CVOTs, dipeptidyl peptidase 4 inhibitors (DPP4i) have been shown to be safe but not to improve mortality/morbidity, except for saxagliptin which increased the risk of HF. Several glucagon-like peptide-1 receptor agonists (GLP1-Ra) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been demonstrated to reduce the risk of cardiovascular mortality and morbidity. SGLT2i have shown a class effect for the reduction in risk of HF events in patients with T2DM, leading to trials testing their efficacy/safety in HF regardless of T2DM. In the DAPA-HF and the EMPEROR-Reduced trials dapagliflozin and empagliflozin, respectively, improved cardiovascular mortality/morbidity in patients with HF with reduced ejection fraction (HFrEF), with and without T2DM. Therefore, these drugs are now key part of HFrEF pharmacotherapy. In the SOLOIST-WHF, sotagliflozin reduced cardiovascular mortality/morbidity in patients with T2DM and a recent acute episode of HF regardless of ejection fraction (EF). In the EMPEROR-Preserved, empagliflozin reduced CV mortality/morbidity in patients with heart failure with mildly reduced (HFmrEF) and preserved (HFpEF) EF regardless of comorbid T2DM. The DELIVER is currently testing dapagliflozin in patients with HFmrEF and HFrEF. A strong renal protective role of SGLT2i has also emerged in trials enrolling patients with and without T2DM.

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Cardiovasc Res: 27 Jul 2022; 118:2231-2252
Savarese G, Butler J, Lund LH, Bhatt DL, Anker SD
Cardiovasc Res: 27 Jul 2022; 118:2231-2252 | PMID: 34390570
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Abstract

Ischaemic tissue released microvesicles induce monocyte reprogramming and increase tissue repair by a tissue factor-dependent mechanism.

Arderiu G, Peña E, Badimon L
Aims
Despite increasing evidence that monocytes may acquire endothelial features, it remains unclear how monocytes participate in angiogenesis after ischaemic damage. We investigated whether ischaemic cells can release microvesicles (MVs) and promote neovascularization in a model of peripheral artery disease (PAD).
Methods and results
To model PAD, we used an in vivo experimental model of hind-limb ischaemia (HLI) in mice. MVs were isolated from the ischaemic muscle and from peripheral blood at different times after unilateral femoral artery ligation. MVs were phenotypically characterized to identify cell origin. HLI in mice induced the release of MVs with a much higher content of tissue factor (TF) than non-HLI control mice both in the MVs isolated from the affected limb muscle area and from blood. MVs were mainly released from endothelial cells (ECs) and induced Mo differentiation to endothelial cell-like (ECL) cells. Differentiation to ECL cells encompassed highly strict hierarchical transcription factor activation, initiated by ETS1 activation. MVs secreted by microvascular ECs over-expressing TF (upTF-EMVs), were injected in the ischaemic hind-limb in parallel with control EMVs (from random siRNA-treated cells) or EMVs released by silenced TF ECs. In animals treated with upTF-EMVs in the ischaemic zone, there was a highly significant increase in functional new vessels formation (seen by magnetic resonance angiography), a concomitant increase in the pool of circulating Ly6Clow Mo expressing vascular EC markers, and a significantly higher number of Mo/macrophages surrounding and integrating the newly formed collaterals.
Conclusion
Ischaemia-activated ECs release EMVs rich in TF that induce monocyte differentiation into ECL cells and the formation of new vessels in the ischaemic zone. TF by this mechanism of formation of new blood microvessels can contribute to ischaemic tissue repair.

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Cardiovasc Res: 27 Jul 2022; 118:2354-2366
Arderiu G, Peña E, Badimon L
Cardiovasc Res: 27 Jul 2022; 118:2354-2366 | PMID: 34406379
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Abstract

MMP-2 knockdown blunts age-dependent carotid stiffness by decreasing elastin degradation and augmenting eNOS activation.

Diaz-Canestro C, Puspitasari YM, Liberale L, Guzik TJ, ... Sudano I, Camici GG
Aims
Arterial stiffness is a hallmark of vascular ageing that precedes and strongly predicts the development of cardiovascular diseases. Age-dependent stiffening of large elastic arteries is primarily attributed to increased levels of matrix metalloproteinase-2 (MMP-2). However, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear. Thus, we aimed to investigate the efficacy of MMP-2 knockdown using small-interfering RNA (siRNA) on age-dependent arterial stiffness.
Methods and results
Pulse wave velocity (PWV) was assessed in right carotid artery of wild-type (WT) mice from different age groups. MMP-2 levels in the carotid artery and plasma of young (3 months) and old (20-25 months) WT mice were determined. Carotid PWV as well as vascular and circulating MMP-2 were elevated with increasing age in mice. Old WT mice (18- to 21-month old) were treated for 4 weeks with either MMP-2 or scrambled (Scr) siRNA via tail vein injection. Carotid PWV was assessed at baseline, 2 and 4 weeks after start of the treatment. MMP-2 knockdown reduced vascular MMP-2 levels and attenuated age-dependent carotid stiffness. siMMP-2-treated mice showed increased elastin-to-collagen ratio, lower plasma desmosine (DES), enhanced phosphorylation of endothelial nitric oxide synthase (eNOS), and higher levels of vascular cyclic guanosine monophosphate (cGMP). An age-dependent increase in direct protein-protein interaction between MMP-2 and eNOS was also observed. Lastly, DES, an elastin breakdown product, was measured in a patient cohort (n = 64, 23-86 years old), where carotid-femoral PWV was also assessed; here, plasma levels of DES directly correlated with age and arterial stiffness.
Conclusion
MMP-2 knockdown attenuates age-dependent carotid stiffness by blunting elastin degradation and augmenting eNOS bioavailability. Given the increasing clinical use of siRNA technology, MMP2 knockdown should be investigated further as a possible strategy to mitigate age-dependent arterial stiffness and related CV diseases.

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Cardiovasc Res: 27 Jul 2022; 118:2385-2396
Diaz-Canestro C, Puspitasari YM, Liberale L, Guzik TJ, ... Sudano I, Camici GG
Cardiovasc Res: 27 Jul 2022; 118:2385-2396 | PMID: 34586381
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Abstract

Non-coding RNAs in cardiac inflammation: key drivers in the pathophysiology of heart failure.

Sansonetti M, De Windt LJ
Heart failure is among the most progressive diseases and a leading cause of morbidity. Despite several advances in cardiovascular therapies, pharmacological treatments are limited to relieve symptoms without curing cardiac injury. Multiple observations point to the involvement of immune cells as key drivers in the pathophysiology of heart failure. In particular, there is a growing recognition that heart failure is related to a prolonged and insufficiently repressed inflammatory response leading to molecular, cellular, and functional cardiac alterations. Over the last decades, non-coding RNAs are recognized as prominent mediators of cardiac inflammation, affecting the function of several immune cells. In the current review, we explore the contribution of the diverse immune cells in the progression of heart failure, revealing mechanistic functions for non-coding RNAs in cardiac immune cells as a new and exciting field of investigation.

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Cardiovasc Res: 20 Jul 2022; 118:2058-2073
Sansonetti M, De Windt LJ
Cardiovasc Res: 20 Jul 2022; 118:2058-2073 | PMID: 34097013
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Abstract

Adiponectin and cardiometabolic trait and mortality: where do we go?

Jang AY, Scherer PE, Kim JY, Lim S, Koh KK
Adiponectin is an adipocyte-derived cytokine known for its cardioprotective effects in preclinical studies. Early epidemiologic studies replicated these findings and drew great interest. Subsequent large-scale prospective cohorts, however, showed that adiponectin levels seemed not to relate to incident coronary artery disease (CAD). Even more surprisingly, a paradoxical increase of all-cause and cardiovascular (CV) mortality with increased adiponectin levels was reported. The adiponectin-mortality paradox has been explained by some groups asserting that adiponectin secretion is promoted by elevated natriuretic peptides (NP). Other groups have proposed that adiponectin is elevated due to adiponectin resistance in subjects with metabolic syndrome or heart failure (HF). However, there is no unifying theory that can clearly explain this paradox. In patients with HF with reduced ejection fraction (HFrEF), stretched cardiomyocytes secrete NPs, which further promote release of adiponectin from adipose tissue, leading to adiponectin resistance. On the other hand, adiponectin biology may differ in patients with heart failure with preserved ejection fraction (HFpEF), which constitutes 50% of all of HF. Most HFpEF patients are obese, which exerts inflammation and myocardial stiffness, i.e. likely to prevent myocardial stretch and subsequent NP release. This segment of the patient population may display different adiponectin biology from its HFrEF counterpart. Dissecting the adiponectin-mortality relationship in terms of different HF subtypes may help to comprehensively understand this paradox. Mendelian randomization (MR) analyses claimed that adiponectin levels are not causally related to CAD or metabolic syndrome. Results from MR studies, however, should be interpreted with great caution because the underlying history of CAD or CHF was not taken into account in these analyses, an issue that may substantially confound the results. Here, we discuss many aspects of adiponectin; cardiometabolic traits, therapeutic interventions, and the ongoing debate about the adiponectin paradox, which were recently described in basic, epidemiologic, and clinical studies.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2074-2084
Jang AY, Scherer PE, Kim JY, Lim S, Koh KK
Cardiovasc Res: 20 Jul 2022; 118:2074-2084 | PMID: 34117867
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Abstract

Interleukin-5-induced eosinophil population improves cardiac function after myocardial infarction.

Xu JY, Xiong YY, Tang RJ, Jiang WY, ... Li XD, Yang YJ
Aims
Interleukin (IL)-5 mediates the development of eosinophils (EOS) that are essential for tissue post-injury repair. It remains unknown whether IL-5 plays a role in heart repair after myocardial infarction (MI). This study aims to test whether IL-5-induced EOS population promotes the healing and repair process post-MI and to reveal the underlying mechanisms.
Methods and results
MI was induced by permanent ligation of the left anterior descending coronary artery in wild-type C57BL/6 mice. Western blot and real-time polymerase chain reaction revealed elevated expression of IL-5 in the heart at 5 days post-MI. Immunohistostaining indicated that IL-5 was secreted mainly from macrophages and CD127+ cells in the setting of experimental MI. External supply of recombinant mouse IL-5 (20 min, 1 day, and 2 days after MI surgery) reduced the infarct size and increased ejection fraction and angiogenesis in the border zone. A significant expansion of EOS was detected in both the peripheral blood and infarcted myocardium after IL-5 administration. Pharmacological depletion of EOS by TRFK5 pretreatment muted the beneficial effects of IL-5 in MI mice. Mechanistic studies demonstrated that IL-5 increased the accumulation of CD206+ macrophages in infarcted myocardium at 7 days post-MI. In vitro co-culture experiments showed that EOS shifted bone marrow-derived macrophage polarization towards the CD206+ phenotypes. This activity of EOS was abolished by IL-4 neutralizing antibody, but not IL-10 or IL-13 neutralization. Western blot analyses demonstrated that EOS promoted the macrophage downstream signal transducer and activator of transcription 6 (STAT6) phosphorylation.
Conclusion
IL-5 facilitates the recovery of cardiac dysfunction post-MI by promoting EOS accumulation and subsequent CD206+ macrophage polarization via the IL-4/STAT6 axis.

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Cardiovasc Res: 20 Jul 2022; 118:2165-2178
Xu JY, Xiong YY, Tang RJ, Jiang WY, ... Li XD, Yang YJ
Cardiovasc Res: 20 Jul 2022; 118:2165-2178 | PMID: 34259869
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Abstract

Nicotine promotes vascular calcification via intracellular Ca2+-mediated, Nox5-induced oxidative stress, and extracellular vesicle release in vascular smooth muscle cells.

Petsophonsakul P, Burgmaier M, Willems B, Heeneman S, ... Furmanik M, Schurgers L
Aims
Smokers are at increased risk of cardiovascular events. However, the exact mechanisms through which smoking influences cardiovascular disease resulting in accelerated atherosclerosis and vascular calcification are unknown. The aim of this study was to investigate effects of nicotine on initiation of vascular smooth muscle cell (VSMC) calcification and to elucidate underlying mechanisms.
Methods and results
We assessed vascular calcification of 62 carotid lesions of both smoking and non-smoking patients using ex vivo micro-computed tomography (µCT) scanning. Calcification was present more often in carotid plaques of smokers (n = 22 of 30, 73.3%) compared to non-smokers (n = 11 of 32, 34.3%; P < 0.001), confirming higher atherosclerotic burden. The difference was particularly profound for microcalcifications, which was 17-fold higher in smokers compared to non-smokers. In vitro, nicotine-induced human primary VSMC calcification, and increased osteogenic gene expression (Runx2, Osx, BSP, and OPN) and extracellular vesicle (EV) secretion. The pro-calcifying effects of nicotine were mediated by Ca2+-dependent Nox5. SiRNA knock-down of Nox5 inhibited nicotine-induced EV release and calcification. Moreover, pre-treatment of hVSMCs with vitamin K2 ameliorated nicotine-induced intracellular oxidative stress, EV secretion, and calcification. Using nicotinic acetylcholine receptor (nAChR) blockers α-bungarotoxin and hexamethonium bromide, we found that the effects of nicotine on intracellular Ca2+ and oxidative stress were mediated by α7 and α3 nAChR. Finally, we showed that Nox5 expression was higher in carotid arteries of smokers and correlated with calcification levels in these vessels.
Conclusion
In this study, we provide evidence that nicotine induces Nox5-mediated pro-calcific processes as novel mechanism of increased atherosclerotic calcification. We identified that activation of α7 and α3 nAChR by nicotine increases intracellular Ca2+ and initiates calcification of hVSMCs through increased Nox5 activity, leading to oxidative stress-mediated EV release. Identifying the role of Nox5-induced oxidative stress opens novel avenues for diagnosis and treatment of smoking-induced cardiovascular disease.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 20 Jul 2022; 118:2196-2210
Petsophonsakul P, Burgmaier M, Willems B, Heeneman S, ... Furmanik M, Schurgers L
Cardiovasc Res: 20 Jul 2022; 118:2196-2210 | PMID: 34273166
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Abstract

The size of apolipoprotein (a) is an independent determinant of the reduction in lipoprotein (a) induced by PCSK9 inhibitors.

Blanchard V, Chemello K, Hollstein T, Hong-Fong CC, ... Steinhagen-Thiessen E, Lambert G
Aims
Lipoprotein (a) [Lp(a)] is a lipoprotein species causatively associated with atherosclerosis. Unlike statins, PCSK9 inhibitors (PCSK9i) reduce Lp(a), but this reduction is highly variable. Levels of Lp(a) are chiefly governed by the size of its signature protein, apolipoprotein (a) [apo(a)]. Whether this parameter determines some of the reduction in Lp(a) induced by PCSK9i remains unknown. We aimed to investigate if the Lp(a) lowering efficacy of PCSK9i is modulated by the size of apo(a), which is genetically determined by the variable number of KIV domains present on that protein.
Methods and results
The levels of Lp(a) and the size of apo(a) were assessed in plasma samples from 268 patients before and after treatment with PCSK9i. Patients were recruited at the Outpatient Lipid Clinic of the Charité Hospital (Berlin) between 2015 and 2020. They were hypercholesterolaemic at very high cardiovascular disease risk with low-density lipoprotein (LDL)-cholesterol levels above therapeutic targets despite maximally tolerated lipid-lowering therapy. Patients received either Alirocumab (75 or 150 mg) or Evolocumab (140 mg) every 2 weeks. Apo(a), apoB100, and apoE concentrations as well as apoE major isoforms were determined by liquid chromatography high-resolution mass spectrometry. Apo(a) isoforms sizes were determined by western blot. PCSK9i sharply reduced LDL-cholesterol (-57%), apoB100 (-47%), and Lp(a) (-36%). There was a positive correlation between the size of apo(a) and the relative reduction in Lp(a) induced by PCSK9i (r = 0.363, P = 0.0001). The strength of this association remained unaltered after adjustment for baseline Lp(a) levels and all other potential confounding factors. In patients with two detectable apo(a) isoforms, there was also a positive correlation between the size of apo(a) and the reduction in Lp(a), separately for the smaller (r = 0.350, P = 0.0001) and larger (r = 0.324, P = 0.0003) isoforms. The relative contribution of the larger isoform to the total concentration of apo(a) was reduced from 29% to 15% (P < 0.0001).
Conclusions
The size of apo(a) is an independent determinant of the response to PCSK9i. Each additional kringle domain is associated with a 3% additional reduction in Lp(a). This explains in part the variable efficacy of PCSK9i and allows to identify patients who will benefit most from these therapies in terms of Lp(a) lowering.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 20 Jul 2022; 118:2103-2111
Blanchard V, Chemello K, Hollstein T, Hong-Fong CC, ... Steinhagen-Thiessen E, Lambert G
Cardiovasc Res: 20 Jul 2022; 118:2103-2111 | PMID: 34314498
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Abstract

Nitro-oleic acid reduces thoracic aortic aneurysm progression in a mouse model of Marfan syndrome.

Nettersheim FS, Lemties J, Braumann S, Geißen S, ... Mollenhauer M, Adam M
Aims
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production, have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS.
Methods and results
Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis, and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+ mice challenged with Angiotensin II.
Conclusion
NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition.

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Cardiovasc Res: 20 Jul 2022; 118:2211-2225
Nettersheim FS, Lemties J, Braumann S, Geißen S, ... Mollenhauer M, Adam M
Cardiovasc Res: 20 Jul 2022; 118:2211-2225 | PMID: 34324651
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Abstract

Cardiac natriuretic peptide deficiency sensitizes the heart to stress-induced ventricular arrhythmias via impaired CREB signalling.

Hall EJ, Pal S, Glennon MS, Shridhar P, ... Lal H, Becker JR
Aims
The cardiac natriuretic peptides [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] are important regulators of cardiovascular physiology, with reduced natriuretic peptide (NP) activity linked to multiple human cardiovascular diseases. We hypothesized that deficiency of either ANP or BNP would lead to similar changes in left ventricular structure and function given their shared receptor affinities.
Methods and results
We directly compared murine models deficient of ANP or BNP in the same genetic backgrounds (C57BL6/J) and environments. We evaluated control, ANP-deficient (Nppa-/-) or BNP-deficient (Nppb-/-) mice under unstressed conditions and multiple forms of pathological myocardial stress. Survival, myocardial structure, function and electrophysiology, tissue histology, and biochemical analyses were evaluated in the groups. In vitro validation of our findings was performed using human-derived induced pluripotent stem cell cardiomyocytes (iPS-CMs). In the unstressed state, both ANP- and BNP-deficient mice displayed mild ventricular hypertrophy which did not increase up to 1 year of life. NP-deficient mice exposed to acute myocardial stress secondary to thoracic aortic constriction (TAC) had similar pathological myocardial remodelling but a significant increase in sudden death. We discovered that the NP-deficient mice are more susceptible to stress-induced ventricular arrhythmias using both in vivo and ex vivo models. Mechanistically, deficiency of either ANP or BNP led to reduced myocardial cGMP levels and reduced phosphorylation of the cAMP response element-binding protein (CREBS133) transcriptional regulator. Selective CREB inhibition sensitized wild-type hearts to stress-induced ventricular arrhythmias. ANP and BNP regulate cardiomyocyte CREBS133 phosphorylation through a cGMP-dependent protein kinase 1 (PKG1) and p38 mitogen-activated protein kinase (p38 MAPK) signalling cascade.
Conclusions
Our data show that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels to regulate cardiomyocyte p38 MAPK and CREB activity. Cardiac natriuretic peptide deficiency leads to a reduction in CREB signalling which sensitizes the heart to stress-induced ventricular arrhythmias.

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Cardiovasc Res: 20 Jul 2022; 118:2124-2138
Hall EJ, Pal S, Glennon MS, Shridhar P, ... Lal H, Becker JR
Cardiovasc Res: 20 Jul 2022; 118:2124-2138 | PMID: 34329394
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Abstract

MicroRNA-27b-3p down-regulates FGF1 and aggravates pathological cardiac remodelling.

Li G, Shao Y, Guo HC, Zhi Y, ... Lai YQ, Li Y
Aims
The heart undergoes pathological remodelling under increased stress and neuronal imbalance. MicroRNAs (miRNAs) are involved in post-transcriptional regulation of genes in cardiac physiology and pathology. However, the mechanisms underlying miRNA-mediated regulation of pathological cardiac remodelling remain to be studied. This study aimed to explore the function of endogenous microRNA-27b-3p (miR-27b-3p) in pathological cardiac remodelling.
Methods and results
miR-27b-3p expression was elevated in the heart of a transverse aortic constriction (TAC)-induced cardiac hypertrophy mouse model. miR-27b-knockout mice showed significantly attenuated cardiac hypertrophy, fibrosis, and inflammation induced by two independent pathological cardiac hypertrophy models, TAC and Angiotensin II (Ang II) perfusion. Transcriptome sequencing analysis revealed that miR-27b deletion significantly down-regulated TAC-induced cardiac hypertrophy, fibrosis, and inflammatory genes. We identified fibroblast growth factor 1 (FGF1) as a miR-27b-3p target gene in the heart which was up-regulated in miR-27b-null mice. We found that both recombinant FGF1 (rFGF1) and inhibition of miR-27b-3p enhanced mitochondrial oxidative phosphorylation (OXPHOS) and inhibited cardiomyocyte hypertrophy. Importantly, rFGF1 administration inhibited cardiac hypertrophy and fibrosis in TAC- or Ang II-induced models and enhanced OXPHOS by activating PGC1α/β.
Conclusions
Our study demonstrated that miR-27b-3p induces pathological cardiac remodelling and suggests that inhibition of endogenous miR-27b-3p or administration of FGF1 might have the potential to suppress cardiac remodelling in a clinical setting.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 20 Jul 2022; 118:2139-2151
Li G, Shao Y, Guo HC, Zhi Y, ... Lai YQ, Li Y
Cardiovasc Res: 20 Jul 2022; 118:2139-2151 | PMID: 34358309
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Abstract

EDIL3 deficiency ameliorates adverse cardiac remodelling by neutrophil extracellular traps (NET)-mediated macrophage polarization.

Wei X, Zou S, Xie Z, Wang Z, ... Cui K, Li J
Aims
After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodelling after MI.
Methods and results
Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodelling, as they exhibited lower mortality, better cardiac function, shorter scar length, and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via Toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodelling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodelling during MI.
Conclusion
We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI.

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Cardiovasc Res: 20 Jul 2022; 118:2179-2195
Wei X, Zou S, Xie Z, Wang Z, ... Cui K, Li J
Cardiovasc Res: 20 Jul 2022; 118:2179-2195 | PMID: 34375400
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Abstract

Culprit site extracellular DNA and microvascular obstruction in ST-elevation myocardial infarction.

Mangold A, Ondracek AS, Hofbauer TM, Scherz T, ... Testori C, Lang IM
Aims
Extracellular chromatin and deoxyribonuclease (DNase) have been identified as important players of thrombosis, inflammation, and homeostasis in a murine model. We previously demonstrated that activated neutrophils release neutrophil extracellular traps (NETs) at the culprit site in ST-elevation myocardial infarction (STEMI), which significantly contribute to extracellular chromatin burden, and are associated with larger infarcts. To understand the correlation between neutrophil activation, extracellular chromatin, and infarct size (IS), we investigated these parameters in a porcine myocardial infarction model, and at different time points and sites in a prospective STEMI trial with cardiac magnetic resonance (CMR) endpoints.
Methods and results
In a prospective STEMI trial (NCT01777750), 101 STEMI patients were included and blood samples were obtained from first medical contact until 6 months after primary percutaneous coronary intervention (pPCI) including direct sampling from the culprit site. CMR was performed 4 ± 2 days and 6 months after pPCI. Neutrophil counts, markers of extracellular chromatin, and inflammation were measured. Double-stranded deoxyribonucleic acid (dsDNA), citrullinated histone 3, nucleosomes, myeloperoxidase, neutrophil elastase, and interleukin (IL)-6 were significantly increased, while DNase activity was significantly decreased at the culprit site in STEMI patients. High neutrophil counts and dsDNA levels at the culprit site correlated with high microvascular obstruction (MVO) and low ejection fraction (EF). High DNase activity at the culprit site correlated with low MVO and high EF. In correspondence, dsDNA correlated with IS in the porcine myocardial infarction model. In porcine infarcts, neutrophils and extracellular chromatin were detected in congested small arteries corresponding with MVO. Markers of neutrophil activation, extracellular chromatin, DNase activity and CMR measurements correlated with markers of systemic inflammation C-reactive protein and IL-6 in patients.
Conclusions
NETs and extracellular chromatin are important determinants of MVO in STEMI. Rapid degradation of extracellular chromatin by DNases appears to be crucial for microvascular patency and outcome.

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Cardiovasc Res: 29 Jun 2022; 118:2006-2017
Mangold A, Ondracek AS, Hofbauer TM, Scherz T, ... Testori C, Lang IM
Cardiovasc Res: 29 Jun 2022; 118:2006-2017 | PMID: 34173822
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Abstract

mRNA modifications in cardiovascular biology and disease: with a focus on m6A modification.

Kumari R, Ranjan P, Suleiman ZG, Goswami SK, ... Prasad R, Verma SK
Among several known RNA modifications, N6-methyladenosine (m6A) is the most studied RNA epitranscriptomic modification and controls multiple cellular functions during development, differentiation, and disease. Current research advancements have made it possible to examine the regulatory mechanisms associated with RNA methylation and reveal its functional consequences in the pathobiology of many diseases, including heart failure. m6A methylation has been described both on coding (mRNA) and non-coding RNA species including rRNA, tRNA, small nuclear RNA and circular RNAs. The protein components which catalyze the m6A methylation are termed methyltransferase or \'m6A writers\'. The family of proteins that recognize this methylation are termed \'m6A readers\' and finally the enzymes involved in the removal of a methyl group from RNA are known as demethylases or \'m6A erasers\'. At the cellular level, different components of methylation machinery are tightly regulated by many factors to maintain the m6A methylation dynamics. The m6A methylation process impacts different stages of mRNA metabolism and the biogenesis of long non-coding RNA and miRNA. Although, mRNA methylation was initially described in the 1970s, its regulatory roles in various diseases, including cardiovascular diseases are broadly unexplored. Recent investigations suggest the important role of m6A mRNA methylation in both hypertrophic and ischaemic heart diseases. In the present review, we evaluate the significance of m6A methylation in the cardiovascular system, in cardiac homeostasis and disease, all of which may help to improve therapeutic intervention for the treatment of heart failure. RNA methylation in cardiovascular diseases: altered m6A RNA (coding and non-coding RNA) methylation is identified during different cardiovascular diseases. Increased cardiac hypertrophy is observed following METTL3 overexpression. In contrast, reduced FTO level was seen in mice following myocardial infarction. Increased cardiac fibroblasts activation or increased atherosclerotic plaques were also co-related with m6A RNA methylation.

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Cardiovasc Res: 22 Jun 2022; 118:1680-1692
Kumari R, Ranjan P, Suleiman ZG, Goswami SK, ... Prasad R, Verma SK
Cardiovasc Res: 22 Jun 2022; 118:1680-1692 | PMID: 33956076
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Abstract

Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy.

Wiedmann F, Beyersdorf C, Zhou XB, Kraft M, ... Katus HA, Schmidt C
Aims
TASK-1 (K2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In this study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF.
Methods and results
Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 days of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 days of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram.
Conclusion
Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.

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Cardiovasc Res: 22 Jun 2022; 118:1728-1741
Wiedmann F, Beyersdorf C, Zhou XB, Kraft M, ... Katus HA, Schmidt C
Cardiovasc Res: 22 Jun 2022; 118:1728-1741 | PMID: 34028533
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Abstract

Non-invasive transcutaneous vagal nerve stimulation improves myocardial performance in doxorubicin-induced cardiotoxicity.

Lai Y, Zhou X, Guo F, Jin X, ... Yu L, Jiang H
Aims
The clinical use of antitumour agent doxorubicin (DOX) is hampered by its dose-dependent cardiotoxicity. Development of highly efficient and safe adjuvant intervention for preventing DOX-induced adverse cardiac events is urgently needed. We aimed to investigate whether transcutaneous vagal nerve stimulation (tVNS) plays a cardio-protective role in DOX-induced cardiotoxicity.
Methods and results
Healthy male adult Sprague Dawley rats were used in the experiment and were randomly divided into four groups including control, DOX, tVNS, and DOX+tVNS groups. A cumulative dose of 15 mg/kg DOX was intraperitoneally injected into rats to generate cardiotoxicity. Non-invasive tVNS was conducted for 6 weeks (30 min/day). After 6-week intervention, the indices from the echocardiography revealed that tVNS significantly improved left ventricular function compared to the DOX group. The increased malondialdehyde and Interleukin-1β, and decreased superoxide dismutase were observed in the DOX group, while tVNS significantly prevented these changes. From cardiac histopathological analysis, the DOX+tVNS group showed a mild myocardial damage, and decreases in cardiac fibrosis and myocardial apoptosis compared to the DOX group. Heart rate variability analysis showed that tVNS significantly inhibited DOX-induced sympathetic hyperactivity compared to the DOX group. Additionally, the results of RNA-sequencing analysis showed that there were 245 differentially expressed genes in the DOX group compared to the control group, among which 39 genes were down-regulated by tVNS and most of these genes were involved in immune system. Moreover, tVNS significantly down-regulated the relative mRNA expressions of chemokine-related genes and macrophages recruitment compared to the DOX group.
Conclusion
These results suggest that tVNS prevented DOX-induced cardiotoxicity by rebalancing autonomic tone, ameliorating cardiac dysfunction and remodelling. Notably, crosstalk between autonomic neuromodulation and innate immune cells macrophages mediated by chemokines might be involved in the underlying mechanisms.

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Cardiovasc Res: 22 Jun 2022; 118:1821-1834
Lai Y, Zhou X, Guo F, Jin X, ... Yu L, Jiang H
Cardiovasc Res: 22 Jun 2022; 118:1821-1834 | PMID: 34145895
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Abstract

Efficacy and limitations of senolysis in atherosclerosis.

Garrido AM, Kaistha A, Uryga AK, Oc S, ... Jørgensen H, Bennett M
Aims
Traditional markers of cell senescence including p16, Lamin B1, and senescence-associated beta galactosidase (SAβG) suggest very high frequencies of senescent cells in atherosclerosis, while their removal via \'senolysis\' has been reported to reduce atherogenesis. However, selective killing of a variety of different cell types can exacerbate atherosclerosis. We therefore examined the specificity of senescence markers in vascular smooth muscle cells (VSMCs) and the effects of genetic or pharmacological senolysis in atherosclerosis.
Methods and results
We examined traditional senescence markers in human and mouse VSMCs in vitro, and in mouse atherosclerosis. p16 and SAβG increased and Lamin B1 decreased in replicative senescence and stress-induced premature senescence (SIPS) of cultured human VSMCs. In contrast, mouse VSMCs undergoing SIPS showed only modest p16 up-regulation, and proliferating mouse monocyte/macrophages also expressed p16 and SAβG. Single cell RNA-sequencing (scRNA-seq) of lineage-traced mice showed increased p16 expression in VSMC-derived cells in plaques vs. normal arteries, but p16 localized to Stem cell antigen-1 (Sca1)+ or macrophage-like populations. Activation of a p16-driven suicide gene to remove p16+ vessel wall- and/or bone marrow-derived cells increased apoptotic cells, but also induced inflammation and did not change plaque size or composition. In contrast, the senolytic ABT-263 selectively reduced senescent VSMCs in culture, and markedly reduced atherogenesis. However, ABT-263 did not reduce senescence markers in vivo, and significantly reduced monocyte and platelet counts and interleukin 6 as a marker of systemic inflammation.
Conclusions
We show that genetic and pharmacological senolysis have variable effects on atherosclerosis, and may promote inflammation and non-specific effects respectively. In addition, traditional markers of cell senescence such as p16 have significant limitations to identify and remove senescent cells in atherosclerosis, suggesting that senescence studies in atherosclerosis and new senolytic drugs require more specific and lineage-restricted markers before ascribing their effects entirely to senolysis.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 22 Jun 2022; 118:1713-1727
Garrido AM, Kaistha A, Uryga AK, Oc S, ... Jørgensen H, Bennett M
Cardiovasc Res: 22 Jun 2022; 118:1713-1727 | PMID: 34142149
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Abstract

Chronically elevated branched chain amino acid levels are pro-arrhythmic.

Portero V, Nicol T, Podliesna S, Marchal GA, ... Potter PK, Remme CA
Aims
Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke, and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach.
Methods and results
We employed a phenotype-driven N-ethyl-N-nitrosourea mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs-leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to electrocardiogram indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs), and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation.
Conclusions
Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome, and heart failure.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 22 Jun 2022; 118:1742-1757
Portero V, Nicol T, Podliesna S, Marchal GA, ... Potter PK, Remme CA
Cardiovasc Res: 22 Jun 2022; 118:1742-1757 | PMID: 34142125
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Impact:
Abstract

Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure.

Couch LS, Fiedler J, Chick G, Clayton R, ... Thum T, Harding SE
Aims 
Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and in the absence of culprit coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS.
Methods and results 
miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal), cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4), and G-protein subunit Gβ (GNB1) as underlying these effects.
Conclusion
miR-16 and miR-26a sensitize the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 22 Jun 2022; 118:1758-1770
Couch LS, Fiedler J, Chick G, Clayton R, ... Thum T, Harding SE
Cardiovasc Res: 22 Jun 2022; 118:1758-1770 | PMID: 34155498
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Impact:
Abstract

Different cardiovascular and pulmonary phenotypes for single- and double-knock-out mice deficient in BMP9 and BMP10.

Bouvard C, Tu L, Rossi M, Desroches-Castan A, ... Guignabert C, Bailly S
Aims
BMP9 and BMP10 mutations were recently identified in patients with pulmonary arterial hypertension, but their specific roles in the pathogenesis of the disease are still unclear. We aimed to study the roles of BMP9 and BMP10 in cardiovascular homeostasis and pulmonary hypertension using transgenic mouse models deficient in Bmp9 and/or Bmp10.
Methods and results
Single- and double-knockout mice for Bmp9 (constitutive) and/or Bmp10 (tamoxifen inducible) were generated. Single-knock-out (KO) mice developed no obvious age-dependent phenotype when compared with their wild-type littermates. However, combined deficiency in Bmp9 and Bmp10 led to vascular defects resulting in a decrease in peripheral vascular resistance and blood pressure and the progressive development of high-output heart failure and pulmonary hemosiderosis. RNAseq analysis of the lungs of the double-KO mice revealed differential expression of genes involved in inflammation and vascular homeostasis. We next challenged these mice to chronic hypoxia. After 3 weeks of hypoxic exposure, Bmp10-cKO mice showed an enlarged heart. However, although genetic deletion of Bmp9 in the single- and double-KO mice attenuated the muscularization of pulmonary arterioles induced by chronic hypoxia, we observed no differences in Bmp10-cKO mice. Consistent with these results, endothelin-1 levels were significantly reduced in Bmp9 deficient mice but not Bmp10-cKO mice. Furthermore, the effects of BMP9 on vasoconstriction were inhibited by bosentan, an endothelin receptor antagonist, in a chick chorioallantoic membrane assay.
Conclusions
Our data show redundant roles for BMP9 and BMP10 in cardiovascular homeostasis under normoxic conditions (only combined deletion of both Bmp9 and Bmp10 was associated with severe defects) but highlight specific roles under chronic hypoxic conditions. We obtained evidence that BMP9 contributes to chronic hypoxia-induced pulmonary vascular remodelling, whereas BMP10 plays a role in hypoxia-induced cardiac remodelling in mice.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 22 Jun 2022; 118:1805-1820
Bouvard C, Tu L, Rossi M, Desroches-Castan A, ... Guignabert C, Bailly S
Cardiovasc Res: 22 Jun 2022; 118:1805-1820 | PMID: 34086873
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Impact:
Abstract

Hooked on heart regeneration: the zebrafish guide to recovery.

Ross Stewart KM, Walker SL, Baker AH, Riley PR, Brittan M
While humans lack sufficient capacity to undergo cardiac regeneration following injury, zebrafish can fully recover from a range of cardiac insults. Over the past two decades, our understanding of the complexities of both the independent and co-ordinated injury responses by multiple cardiac tissues during zebrafish heart regeneration has increased exponentially. Although cardiomyocyte regeneration forms the cornerstone of the reparative process in the injured zebrafish heart, recent studies have shown that this is dependent on prior neovascularization and lymphangiogenesis, which in turn require epicardial, endocardial, and inflammatory cell signalling within an extracellular milieu that is optimized for regeneration. Indeed, it is the amalgamation of multiple regenerative systems and gene regulatory patterns that drives the much-heralded success of the adult zebrafish response to cardiac injury. Increasing evidence supports the emerging paradigm that developmental transcriptional programmes are re-activated during adult tissue regeneration, including in the heart, and the zebrafish represents an optimal model organism to explore this concept. In this review, we summarize recent advances from the zebrafish cardiovascular research community with novel insight into the mechanisms associated with endogenous cardiovascular repair and regeneration, which may be of benefit to inform future strategies for patients with cardiovascular disease.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 22 Jun 2022; 118:1667-1679
Ross Stewart KM, Walker SL, Baker AH, Riley PR, Brittan M
Cardiovasc Res: 22 Jun 2022; 118:1667-1679 | PMID: 34164652
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Impact:
Abstract

Discovery of a first-in-class inhibitor of sulfide:quinone oxidoreductase that protects against adverse cardiac remodelling and heart failure.

Jackson MR, Cox KD, Baugh SDP, Wakeen L, ... Polyak B, Jorns MS
Aims
Hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by post-translational modification (persulfidation) of cysteine residues in upstream protein targets. Heart failure patients with reduced ejection fraction (HFrEF) exhibit low levels of H2S. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling. Here, the aim of this study was to discover a first-in-class inhibitor of human SQOR and evaluate its cardioprotective effect in an animal model of HFrEF.
Methods and results
We identified a potent inhibitor of human SQOR (STI1, IC50 = 29 nM) by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. STI1 is a competitive inhibitor that binds with high selectivity to the coenzyme Q-binding pocket in SQOR. STI1 exhibited very low cytotoxicity and attenuated the hypertrophic response of neonatal rat ventricular cardiomyocytes and H9c2 cells induced by neurohormonal stressors. A mouse HFrEF model was produced by transverse aortic constriction (TAC). Treatment of TAC mice with STI1 mitigated the development of cardiomegaly, pulmonary congestion, dilatation of the left ventricle, and cardiac fibrosis and decreased the pressure gradient across the aortic constriction. Moreover, STI1 dramatically improved survival, preserved cardiac function, and prevented the progression to HFrEF by impeding the transition from compensated to decompensated left ventricle hypertrophy.
Conclusion
We demonstrate that the coenzyme Q-binding pocket in human SQOR is a druggable target and establish proof of concept for the potential of SQOR inhibitors to provide a novel therapeutic approach for the treatment of HFrEF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 22 Jun 2022; 118:1771-1784
Jackson MR, Cox KD, Baugh SDP, Wakeen L, ... Polyak B, Jorns MS
Cardiovasc Res: 22 Jun 2022; 118:1771-1784 | PMID: 34132787
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Abstract

Loss of Yap/Taz in cardiac fibroblasts attenuates adverse remodelling and improves cardiac function.

Mia MM, Cibi DM, Ghani SABA, Singh A, ... Mao J, Singh MK
Aims
Fibrosis is associated with all forms of adult cardiac diseases including myocardial infarction (MI). In response to MI, the heart undergoes ventricular remodelling that leads to fibrotic scar due to excessive deposition of extracellular matrix mostly produced by myofibroblasts. The structural and mechanical properties of the fibrotic scar are critical determinants of heart function. Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) are the key effectors of the Hippo signalling pathway and are crucial for cardiomyocyte proliferation during cardiac development and regeneration. However, their role in cardiac fibroblasts, regulating post-MI fibrotic and fibroinflammatory response, is not well established.
Methods and results
Using mouse model, we demonstrate that Yap/Taz are activated in cardiac fibroblasts after MI and fibroblasts-specific deletion of Yap/Taz using Col1a2Cre(ER)T mice reduces post-MI fibrotic and fibroinflammatory response and improves cardiac function. Consistently, Yap overexpression elevated post-MI fibrotic response. Gene expression profiling shows significant downregulation of several cytokines involved in post-MI cardiac remodelling. Furthermore, Yap/Taz directly regulate the promoter activity of pro-fibrotic cytokine interleukin-33 (IL33) in cardiac fibroblasts. Blocking of IL33 receptor ST2 using the neutralizing antibody abrogates the Yap-induced pro-fibrotic response in cardiac fibroblasts. We demonstrate that the altered fibroinflammatory programme not only affects the nature of cardiac fibroblasts but also the polarization as well as infiltration of macrophages in the infarcted hearts. Furthermore, we demonstrate that Yap/Taz act downstream of both Wnt and TGFβ signalling pathways in regulating cardiac fibroblasts activation and fibroinflammatory response.
Conclusion
We demonstrate that Yap/Taz play an important role in controlling MI-induced cardiac fibrosis by modulating fibroblasts proliferation, transdifferentiation into myofibroblasts, and fibroinflammatory programme.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 22 Jun 2022; 118:1785-1804
Mia MM, Cibi DM, Ghani SABA, Singh A, ... Mao J, Singh MK
Cardiovasc Res: 22 Jun 2022; 118:1785-1804 | PMID: 34132780
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Abstract

Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling.

Ljubojević-Holzer S, Kraler S, Djalinac N, Abdellatif M, ... Maack C, Sedej S
Aims
Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure.
Methods and results
RT-qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5-/-). Before manifesting cardiac dysfunction, Atg5-/- mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5-/- cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5-/- cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload.
Conclusion
Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 06 May 2022; 118:1492-1505
Ljubojević-Holzer S, Kraler S, Djalinac N, Abdellatif M, ... Maack C, Sedej S
Cardiovasc Res: 06 May 2022; 118:1492-1505 | PMID: 33752242
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Impact:
Abstract

Anxa1 in smooth muscle cells protects against acute aortic dissection.

Zhou C, Lin Z, Cao H, Chen Y, ... Pan B, Zheng L
Aims
Acute aortic dissection (AAD) is a life-threatening disease with high morbidity and mortality. Previous studies have showed that vascular smooth muscle cell (VSMC) phenotype switching modulates vascular function and AAD progression. However, whether an endogenous signalling system that protects AAD progression exists remains unknown. Our aim is to investigate the role of Anxa1 in VSMC phenotype switching and the pathogenesis of AAD.
Methods and results
We first assessed Anxa1 expression levels by immunohistochemical staining in control aorta and AAD tissue from mice. A strong increase of Anxa1 expression was seen in the mouse AAD tissues. In line with these findings, micro-CT scan results indicated that Anxa1 plays a role in the development of AAD in our murine model, with systemic deficiency of Anxa1 markedly progressing AAD. Conversely, administration of Anxa1 mimetic peptide, Ac2-26, rescued the AAD phenotype in Anxa1-/- mice. Transcriptomic studies revealed a novel role for Anxa1 in VSMC phenotype switching, with Anxa1 deficiency triggering the synthetic phenotype of VSMCs via down-regulation of the JunB/MYL9 pathway. The resultant VSMC synthetic phenotype rendered elevated inflammation and enhanced matrix metalloproteinases (MMPs) production, leading to augmented elastin degradation. VSMC-restricted deficiency of Anxa1 in mice phenocopied VSMC phenotype switching and the consequent exacerbation of AAD. Finally, our studies in human AAD aortic specimens recapitulated key findings in murine AAD, specifically that the decrease of Anxa1 is associated with VSMC phenotype switch, heightened inflammation, and enhanced MMP production in human aortas.
Conclusions
Our findings demonstrated that Anxa1 is a novel endogenous defender that prevents AAD by inhibiting VSMC phenotype switching, suggesting that Anxa1 signalling may be a potential target for AAD pharmacological therapy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 06 May 2022; 118:1564-1582
Zhou C, Lin Z, Cao H, Chen Y, ... Pan B, Zheng L
Cardiovasc Res: 06 May 2022; 118:1564-1582 | PMID: 33757117
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Abstract

Role of oxidative stress in calcific aortic valve disease and its therapeutic implications.

Greenberg HZE, Zhao G, Shah AM, Zhang M
Calcific aortic valve disease (CAVD) is the end result of active cellular processes that lead to the progressive fibrosis and calcification of aortic valve leaflets. In western populations, CAVD is a significant cause of cardiovascular morbidity and mortality, and in the absence of effective drugs, it will likely represent an increasing disease burden as populations age. As there are currently no pharmacological therapies available for preventing, treating, or slowing the development of CAVD, understanding the mechanisms underlying the initiation and progression of the disease is important for identifying novel therapeutic targets. Recent evidence has emerged of an important causative role for reactive oxygen species (ROS)-mediated oxidative stress in the pathophysiology of CAVD, inducing the differentiation of valve interstitial cells into myofibroblasts and then osteoblasts. In this review, we focus on the roles and sources of ROS driving CAVD and consider their potential as novel therapeutic targets for this debilitating condition.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 06 May 2022; 118:1433-1451
Greenberg HZE, Zhao G, Shah AM, Zhang M
Cardiovasc Res: 06 May 2022; 118:1433-1451 | PMID: 33881501
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Abstract

Primary cilia control endothelial permeability by regulating expression and location of junction proteins.

Diagbouga MR, Morel S, Cayron AF, Haemmerli J, ... Bijlenga P, Kwak BR
Aims
Wall shear stress (WSS) determines intracranial aneurysm (IA) development. Polycystic kidney disease (PKD) patients have a high IA incidence and risk of rupture. Dysfunction/absence of primary cilia in PKD endothelial cells (ECs) may impair mechano-transduction of WSS and favour vascular disorders. The molecular links between primary cilia dysfunction and IAs are unknown.
Methods and results
Wild-type and primary cilia-deficient Tg737orpk/orpk arterial ECs were submitted to physiological (30 dynes/cm2) or aneurysmal (2 dynes/cm2) WSS, and unbiased transcriptomics were performed. Tg737orpk/orpk ECs displayed a fivefold increase in the number of WSS-responsive genes compared to wild-type cells. Moreover, we observed a lower trans-endothelial resistance and a higher endothelial permeability, which correlated with disorganized intercellular junctions in Tg737orpk/orpk cells. We identified ZO-1 as a central regulator of primary cilia-dependent endothelial junction integrity. Finally, clinical and histological characteristics of IAs from non-PKD and PKD patients were analysed. IAs in PKD patients were more frequently located in the middle cerebral artery (MCA) territory than in non-PKD patients. IA domes from the MCA of PKD patients appeared thinner with less collagen and reduced endothelial ZO-1 compared with IA domes from non-PKD patients.
Conclusion
Primary cilia dampen the endothelial response to aneurysmal low WSS. In absence of primary cilia, ZO-1 expression levels are reduced, which disorganizes intercellular junctions resulting in increased endothelial permeability. This altered endothelial function may not only contribute to the severity of IA disease observed in PKD patients, but may also serve as a potential diagnostic tool to determine the vulnerability of IAs.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 06 May 2022; 118:1583-1596
Diagbouga MR, Morel S, Cayron AF, Haemmerli J, ... Bijlenga P, Kwak BR
Cardiovasc Res: 06 May 2022; 118:1583-1596 | PMID: 33974072
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Abstract

Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice.

Fang L, Ohashi K, Otaka N, Ogawa H, ... Murohara T, Ouchi N
Aims 
Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here, we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein E-knockout (apoE-KO) mice.
Methods and results 
apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate apoE-KO/OMT-Tg mice. apoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. apoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apoE-KO mice. apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibres in response to Ang II compared with apoE-KO mice. apoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, and pro-inflammatory genes in aortic walls compared with apoE-KO mice. Furthermore, systemic administration of omentin also attenuated AAA formation and disruption of medial elastic fibres in response to Ang II in apoE-KO mice. Treatment of human monocyte-derived macrophages with omentin protein attenuated expression of MMP9 and pro-inflammatory mediators, and MMP9 activation after stimulation with lipopolysaccharide. Treatment of human vascular smooth muscle cells (VSMCs) with omentin protein reduced expression and activation of MMP2 after stimulation with tumour necrosis factor α. Omentin treatment increased phosphorylation levels of Akt in human macrophages and VSMCs. The suppressive effects of omentin on MMP9 and MMP2 expression were reversed by inhibition of integrin-αVβ3/PI3-kinase/Akt signalling in macrophages and VSMCs, respectively.
Conclusion 
These data suggest that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA through suppression of MMP9 and MMP2 expression and inflammatory response in the vascular wall.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

Cardiovasc Res: 06 May 2022; 118:1597-1610
Fang L, Ohashi K, Otaka N, Ogawa H, ... Murohara T, Ouchi N
Cardiovasc Res: 06 May 2022; 118:1597-1610 | PMID: 34051089
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Abstract

Catheter ablation of short-coupled variant of torsade de pointes.

Steinfurt J, Nazer B, Aguilar M, Moss J, ... Tedrow UB, Bogossian H
Background
The short-coupled variant of torsade de pointes (sc-TdP) is a malignant arrhythmia that frequently presents with ventricular fibrillation (VF) electrical storm. Verapamil is considered the first-line therapy of sc-TdP while catheter ablation is not widely adopted. The aim of this study was to determine the origin of sc-TdP and to assess the outcome of catheter ablation using 3D-mapping.
Methods and results
We retrospectively analyzed five patients with sc-TdP who underwent 3D-mapping and ablation of sc-TdP at five different institutions. Four patients initially presented with sudden cardiac arrest, one patient experienced recurrent syncope as the first manifestation. All patients demonstrated a monomorphic premature ventricular contraction (PVC) with late transition left bundle branch block pattern, superior axis, and a coupling interval of less than 300 ms. triggering recurrent TdP and VF. In four patients, the culprit PVC was mapped to the free wall insertion of the moderator band (MB) with a preceding Purkinje potential in two patients. Catheter ablation using 3D-mapping and intracardiac echocardiography eliminated sc-TdP in all patients, with no recurrence at mean 2.7 years (range 6 months to 8 years) of follow-up.
Conclusion
3D-mapping and intracardiac echocardiography demonstrate that sc-TdP predominantly originates from the MB free wall insertion and its Purkinje network. Catheter ablation of the culprit PVC at the MB free wall junction leads to excellent short- and long-term results and should be considered as first-line therapy in recurrent sc-TdP or electrical storm.

© 2021. The Author(s).

Clin Res Cardiol: 01 May 2022; 111:502-510
Steinfurt J, Nazer B, Aguilar M, Moss J, ... Tedrow UB, Bogossian H
Clin Res Cardiol: 01 May 2022; 111:502-510 | PMID: 33770204
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Abstract

Therapeutic application of genome editing in dyslipidemia.

Whittaker MN, Musunuru K
Purpose of review
To summarize recent advances with respect to the use of genome editing to modify blood lipid levels in vivo.
Recent findings
Genome-editing technologies have been successfully used to target the PCSK9 gene in the livers of nonhuman primates and significantly reduce blood LDL cholesterol levels.
Summary
Multiple proof-of-concept nonhuman primate studies raise the prospect of genome editing empowering \'one-and-done\' therapies for the treatment of dyslipidemic patients.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 01 Apr 2022; 33:133-138
Whittaker MN, Musunuru K
Curr Opin Lipidol: 01 Apr 2022; 33:133-138 | PMID: 34907967
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Impact:
Abstract

Current models of apolipoprotein A-I lipidation by adenosine triphosphate binding cassette transporter A1.

Hafiane A, Gianopoulos I, Sorci-Thomas MG, Daskalopoulou SS
Purpose of review
The primary cardioprotective function of high-density lipoprotein (HDL) is to remove excess cellular free cholesterol (FC) from peripheral tissues and deliver it to the liver. Here, we summarize recent research that examines apolipoprotein A-I (apoA-I) lipidation models by adenosine triphosphate binding cassette transporter A1 (ABCA1) and discuss its relevance in atherosclerotic cardiovascular disease (ASCVD).
Recent findings
The first step in HDL formation involves the interaction between apoA-I and ABCA1, where ABCA1 mediates the removal of FC and phospholipids from lipid-laden macrophages to form discoidal nascent HDL (nHDL). However, there are currently no clear-cut systematic models that characterize HDL formation. A number of recent studies have investigated the importance of apoA-I C- and N-terminal domains required for optimal cholesterol efflux and nHDL production. Furthermore, functional ABCA1 is required for direct or indirect binding to apoA-I where ABCA1 dimer-monomer interconversion facilitates apoA-I lipidation from plasma membrane microdomains. Microparticles are also another lipid source for apoA-I solubilization into nHDL.
Summary
ApoA-I and ABCA1 are key factors in macrophage-mediated cholesterol efflux and nHDL production. Understanding of the key steps in HDL formation may unlock the therapeutic potential of HDL and improve clinical management of ASCVD.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 31 Mar 2022; 33:139-145
Hafiane A, Gianopoulos I, Sorci-Thomas MG, Daskalopoulou SS
Curr Opin Lipidol: 31 Mar 2022; 33:139-145 | PMID: 34581311
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Abstract

Familial combined hyperlipidemia is a polygenic trait.

Gill PK, Hegele RA
Purpose of review
: Familial combined hyperlipidemia (FCH), defined by concurrently elevated plasma triglyceride (TG) and low-density lipoprotein (LDL) cholesterol, has long been investigated to characterize its genetic basis. Despite almost half a century of searching, a single gene cause for the phenotype has not yet been identified.
Recent findings
: Recent studies using next-generation genetic analytic methods confirm that FCH has a polygenic basis, with a clear large contribution from the accumulation of small-to-moderate effect common single nucleotide polymorphisms (SNPs) throughout the genome that is associated with raising TG, and probably also those raising LDL cholesterol. On the other hand, rare monogenic variants, such as those causing familial hypercholesterolemia, play a negligible role, if any. Genetic profiling suggests that patients with FCH and hypertriglyceridemia share a strong polygenic basis and show a similar profile of multiple TG-raising common SNPs.
Summary
: Recent progress in genomics has shown that most if not all of the genetic susceptibility to FCH is polygenic in nature. Future research should include larger cohort studies, with wider ancestral diversity, ancestry-specific polygenic scores, and investigation of epigenetic and lifestyle factors to help further elucidate the causative agents at play in cases where the genetic etiology remains to be defined.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 31 Mar 2022; 33:126-132
Gill PK, Hegele RA
Curr Opin Lipidol: 31 Mar 2022; 33:126-132 | PMID: 34690300
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Abstract

ANGPTL4: a new mode in the regulation of intravascular lipolysis.

Ploug M
Purpose of review
Lipoprotein lipase (LPL) is the rate-limiting enzyme for intravascular processing of circulating triglyceride-rich lipoproteins (TRLs). One emerging strategy for therapeutic lowering of plasma triglyceride levels aims at increasing the longevity of LPL activity by attenuating its inhibition from angiopoietin-like proteins (ANGPTL) 3, 4 and 8. This mini-review focuses on recent insights into the molecular mechanisms underpinning the regulation of LPL activity in the intravascular unit by ANGPTLs with special emphasis on ANGPTL4.
Recent findings
Our knowledge on the molecular interplays between LPL, its endothelial transporter GPIHBP1, and its inhibitor(s) ANGPTL4, ANGPTL3 and ANGPTL8 have advanced considerably in the last 2 years and provides an outlined on how these proteins regulate the activity and compartmentalization of LPL. A decisive determinant instigating this control is the inherent protein instability of LPL at normal body temperature, a property that is reciprocally impacted by the binding of GPIHBP1 and ANGPTLs. Additional layers in this complex LPL regulation is provided by the different modulation of ANGPTL4 and ANGPTL3 activities by ANGPTL8 and the inhibition of ANGPTL3/8 complexes by apolipoprotein A5 (APOA5).
Summary
Posttranslational regulation of LPL activity in the intravascular space is essential for the differential partitioning of TRLs across tissues and their lipolytic processing in response to nutritional cues.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 31 Mar 2022; 33:112-119
Ploug M
Curr Opin Lipidol: 31 Mar 2022; 33:112-119 | PMID: 34860701
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Impact:
Abstract

Rho kinase inhibition ameliorates vascular remodeling and blood pressure elevations in a rat model of apatinib-induced hypertension.

Li C, Ma L, Wang Q, Shao X, ... Wang W, Yu J
Objectives
Hypertension is one of the major adverse effects of tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors. However, the mechanism underlying TKIs-induced hypertension remains unclear. Here, we explored the role of the RhoA/Rho kinase (ROCK) signaling pathway in elevation of blood pressure (BP) induced by apatinib, a selective TKI approved in China for treatment of advanced or metastatic gastric cancer. A nonspecific ROCK inhibitor, Y27632, was then combined with apatinib and its efficacy in alleviating apatinib-induced hypertension was evaluated.
Methods
Normotensive female Wistar-Kyoto rats were exposed to two different doses of apatinib, or apatinib combined with Y27632, or vehicle for 2 weeks. BP was monitored by a tail-cuff plethysmography system. The mRNA levels and protein expression in the RhoA/ROCK pathway were determined, and vascular remodeling assessed.
Results
Administration of either a high or low dose of apatinib was associated with a rapid rise in BP, reaching a plateau after 12 days. Apatinib treatment mediated upregulation of RhoA and ROCK II in the mid-aorta, more significant in the high-dose group. However, ROCK I expression showed no statistically significant differences. Furthermore, the mRNA level of GRAF3 decreased dose-dependently. Apatinib administration was also associated with decreased levels of MLCP, and elevated endothelin-1 (ET-1) and collagen I, which were accompanied with increased mid-aortic media. However, treatment with Y27632 attenuated the above changes.
Conclusion
These findings suggest that activation of the RhoA/ROCK signaling pathway could be the underlying mechanism of apatinib-induced hypertension, while ROCK inhibitor have potential therapeutic value.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.

J Hypertens: 31 Mar 2022; 40:675-684
Li C, Ma L, Wang Q, Shao X, ... Wang W, Yu J
J Hypertens: 31 Mar 2022; 40:675-684 | PMID: 34862331
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Impact:
Abstract

Association of dietary patterns and components with atherosclerosis risk biomarkers in familial hypercholesterolemia.

Antoniazi L, Arroyo-Olivares R, Mata P, Santos RD
Purpose of review
Familial hypercholesterolemia (FH) is a relatively common genetic disorder associated with elevated atherosclerotic risk. Dietary interventions can modulate processes associated with cardiovascular risk and potentiate the impact of pharmacological lipid-lowering therapies. This review evaluates recent findings of dietary patterns and their components on risk biomarkers in people with FH.
Recent findings
Diets lower in saturated fatty acids (SFA) may reduce low-density lipoprotein-cholesterol (LDL-C); however, their effects seem to be modest. A Mediterranean style diet apparently exerts more robust effects on plasma LDL-C, apolipoprotein B and C reactive protein concentrations than one restricted in SFA. Supplementation of plant sterols and stanols reduces LDL-C especially in children with FH. Caloric restricted diets may reduce weight and improve triglyceride levels in individuals with FH and excess body weight.
Summary
Despite the strong impact of genetic variants, dietary patterns mostly low in SFA and especially the Mediterranean diet may influence risk biomarkers in FH. However, most available studies are limited by cross-sectional design, small number of study subjects and short-term follow-ups. Robust interventional studies are necessary to test the impact of dietary patterns in people with FH.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 31 Mar 2022; 33:89-94
Antoniazi L, Arroyo-Olivares R, Mata P, Santos RD
Curr Opin Lipidol: 31 Mar 2022; 33:89-94 | PMID: 34907966
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Impact:
Abstract

Metabolic dysfunction-associated fatty liver disease: advances in genetic and epigenetic implications.

Pirola CJ, Sookoian S
Purpose of review
Fatty liver associated with metabolic dysfunction, also known under the acronym NAFLD (nonalcoholic fatty liver disease) is the leading global cause of chronic liver disease. In this review, we address the state of research on genetics and epigenetics of NAFLD with focus on key discoveries and conceptual advances over the past 2 years.
Recent findings
The analysis of NAFLD-associated genetic variant effects on the whole-transcriptome, including quantitative trait loci (QTL) associated with gene expression (eQTL) or splicing (sQTL) may explain pleiotropic effects. Functional experiments on NAFLD-epigenetics, including profiling of liver chromatin accessibility quantitative trait loci (caQTL) show co-localization with numerous genome-wide association study signals linked to metabolic and cardiovascular traits. Novel studies provide insights into the modulation of the hepatic transcriptome and epigenome by tissue microbiotas. Genetic variation of components of the liver cellular respirasome may result in broad cellular and metabolic effects. Mitochondrial noncoding RNAs may regulate liver inflammation and fibrogenesis. RNA modifications as N6-methyladenosine may explain sex-specific differences in liver gene transcription linked to lipid traits.
Summary
The latest developments in the field of NAFLD-genomics can be leveraged for identifying novel disease mechanisms and therapeutic targets that may prevent the morbidity and mortality associated with disease progression.
Video abstract
http://links.lww.com/COL/A23.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Curr Opin Lipidol: 31 Mar 2022; 33:95-102
Pirola CJ, Sookoian S
Curr Opin Lipidol: 31 Mar 2022; 33:95-102 | PMID: 34966133
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Impact:
Abstract

Mechanism of CircANKRD36 regulating cell heterogeneity and endothelial mesenchymal transition in aortic valve stromal cells by regulating miR-599 and TGF-β signaling pathway.

Zhang C, Liu M, Wang X, Chen S, ... Dong N, Shang X
Objective
To explore the mechanism of CircANKRD36 regulating cell heterogeneity and endothelial mesenchymal transition in aortic valve stromal cells by regulating miR-599 and TGF-β signaling pathway.
Methods
Human tissue specimens were divided into Control group (n = 25) and CAVD group (n = 25). The mRNA expressions of CircANKRD36 and miR-599 in tissue samples were analyzed by qRT-PCR. Western blot was used to analyze the protein expression of osteogenic differentiation related factors induced by OM.The expressions of ALP, osteocalcin, osteopontin, Runx2 and Cadherin11 were detected by Western blot.
Results
The expression of CircANKRD36mRNA in CAVD tissue was lower than that in Control tissue (P < 0.05), and the expression of miR-599mRNA in CAVD tissue was higher than that in Control tissue (P < 0.05). CircANKRD36 was negatively correlated with ALP, osteocalcin, osteopontin, Runx2, Cadherin11 expression level after OM induced osteogenic differentiation. The expression level of miR-599 was positively correlated with ALP, osteocalcin, osteopontin, Runx2 and Cadherin11 after OM induced osteogenic differentiation.The expression of ALP, osteocalcin, osteopontin, Runx2 and Cadherin11 protein in circ+miR-599 group was lower than that in circ+miR-NC group (P < 0.05). Compared with Vector+miR-NC group, the protein expressions of TGF-β1, TGF-β2 and SMAD4 in circ+miR-NC group decreased (P < 0.05), while the protein expressions of TGF-β1, TGF-β2 and SMAD4 in circ+miR-599 group increased (P < 0.05).
Conclusion
CircANKRD36 can inhibit the expression of miR-599 and the activation of TGF-β signaling pathway, thus inhibiting the expression of differentiation-related factors of VIC osteogenesis and the formation of calcified nodules. Therefore, circANKRD36-miR-599-TGF-β axis can be a new theoretical basis for treating CAVD.

Copyright © 2022 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Mar 2022; 352:104-114
Zhang C, Liu M, Wang X, Chen S, ... Dong N, Shang X
Int J Cardiol: 31 Mar 2022; 352:104-114 | PMID: 35074490
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Impact:
Abstract

Estimation of low-density lipoprotein cholesterol levels using machine learning.

Oh GC, Ko T, Kim JH, Lee MH, ... Kim KH, Lee HY
Background
Low-density lipoprotein-cholesterol (LDL-C) is used as a threshold and target for treating dyslipidemia. Although the Friedewald equation is widely used to estimate LDL-C, it has been known to be inaccurate in the case of high triglycerides (TG) or non-fasting states. We aimed to propose a novel method to estimate LDL-C using machine learning.
Methods
Using a large, single-center electronic health record database, we derived a ML algorithm to estimate LDL-C from standard lipid profiles. From 1,029,572 cases with both standard lipid profiles (total cholesterol, high-density lipoprotein-cholesterol, and TG) and direct LDL-C measurements, 823,657 tests were used to derive LDL-C estimation models. Patient characteristics such as sex, age, height, weight, and other laboratory values were additionally used to create separate data sets and algorithms.
Results
Machine learning with gradient boosting (LDL-CX) and neural network (LDL-CN) showed better correlation with directly measured LDL-C, compared with conventional methods (r = 0.9662, 0.9668, 0.9563, 0.9585; for LDL-CX, LDL-CN, Friedewald [LDL-CF], and Martin [LDL-CM] equations, respectively). The overall bias of LDL-CX (-0.27 mg/dL, 95% CI -0.30 to -0.23) and LDL-CN (-0.01 mg/dL, 95% CI -0.04-0.03) were significantly smaller compared with both LDL-CF (-3.80 mg/dL, 95% CI -3.80 to -3.60) or LDL-CM (-2.00 mg/dL, 95% CI -2.00 to -1.94), especially at high TG levels.
Conclusions
Machine learning algorithms were superior in estimating LDL-C compared with the conventional Friedewald or the more contemporary Martin equations. Through external validation and modification, machine learning could be incorporated into electronic health records to substitute LDL-C estimation.

Copyright © 2022 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Mar 2022; 352:144-149
Oh GC, Ko T, Kim JH, Lee MH, ... Kim KH, Lee HY
Int J Cardiol: 31 Mar 2022; 352:144-149 | PMID: 35065153
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Impact:
Abstract

CD36 (SR-B2) as master regulator of cellular fatty acid homeostasis.

Glatz JFC, Nabben M, Luiken JJFP
Purpose of review
Transmembrane glycoprotein cluster of differentiation 36 (CD36) is a scavenger receptor class B protein (SR-B2) that serves various functions in lipid metabolism and signaling, in particular facilitating the cellular uptake of long-chain fatty acids. Recent studies have disclosed CD36 to play a prominent regulatory role in cellular fatty acid metabolism in both health and disease.
Recent findings
The rate of cellular fatty acid uptake is short-term (i.e., minutes) regulated by the subcellular recycling of CD36 between endosomes and the plasma membrane. This recycling is governed by the activity of vacuolar-type H+-ATPase (v-ATPase) in the endosomal membrane via assembly and disassembly of two subcomplexes. The latter process is being influenced by metabolic substrates including fatty acids, glucose and specific amino acids, together resulting in a dynamic interplay to modify cellular substrate preference and uptake rates. Moreover, in cases of metabolic disease v-ATPase activity was found to be affected while interventions aimed at normalizing v-ATPase functioning had therapeutic potential.
Summary
The emerging central role of CD36 in cellular lipid homeostasis and recently obtained molecular insight in the interplay among metabolic substrates indicate the applicability of CD36 as target for metabolic modulation therapy in disease. Experimental studies already have shown the feasibility of this approach.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Curr Opin Lipidol: 31 Mar 2022; 33:103-111
Glatz JFC, Nabben M, Luiken JJFP
Curr Opin Lipidol: 31 Mar 2022; 33:103-111 | PMID: 35125400
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Impact:
Abstract

Tissue-engineered vascular grafts and regeneration mechanisms.

Wei Y, Wang F, Guo Z, Zhao Q
Cardiovascular diseases (CVDs) are life-threatening diseases with high morbidity and mortality worldwide. Vascular bypass surgery is still the ultimate strategy for CVD treatment. Autografts are the gold standard for graft transplantation, but insufficient sources limit their widespread application. Therefore, alternative tissue engineered vascular grafts (TEVGs) are urgently needed. In this review, we summarize the major strategies for the preparation of vascular grafts, as well as the factors affecting their patency and tissue regeneration. Finally, the underlying mechanisms of vascular regeneration that are mediated by host cells are discussed.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 31 Mar 2022; 165:40-53
Wei Y, Wang F, Guo Z, Zhao Q
J Mol Cell Cardiol: 31 Mar 2022; 165:40-53 | PMID: 34971664
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Impact:
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