Journal: J Mol Cell Cardiol

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Abstract

The road to physiological maturation of stem cell-derived cardiac muscle runs through the sarcomere.

Metzger JM
Recent advances the cardiac biomedical sciences have been propelled forward by the development and implementation of human iPSC-derived cardiac muscle. These notable successes notwithstanding, it is well recognized in the field that a major roadblock persists in the lack of full \"adult cardiac muscle-like\" maturation of hiPSC-CMs. This Perspective centers focus on maturation roadblocks in the essential physiological unit of muscle, the sarcomere. Stalled sarcomere maturation must be addressed and overcome before this elegant experimental platform can reach the mountaintop of making impactful contributions in disease pathogenesis, drug discovery, and in clinical regenerative medicine.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 22 Jun 2022; epub ahead of print
Metzger JM
J Mol Cell Cardiol: 22 Jun 2022; epub ahead of print | PMID: 35752207
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Abstract

miR-564: A potential regulator of vascular smooth muscle cells and therapeutic target for aortic dissection.

Li M, Yang Y, Zong J, Wang Z, ... Wang JX, Yu T
Background
Aortic dissection (AD) is a lethal cardiac disorder and one of the most concerning cardiovascular diseases (CVDs). Increasing evidence indicates that human aortic vascular smooth muscle cells (VSMCs) play a crucial role in the pathogenesis of AD, especially related to phenotypic transformation. And notablely, the development of AD is also accompanied by inflammation.
Methods
By using quantitative real-time PCR and fluorescence in situ hybridization (FISH), we detected the expression levels of miR-564 in vitro and in vivo. The effects of miR-564 proliferation and migration were investigated in VSMCs. The downstream targets of miR-564 were found by bioinformatics analyse, and verified in the regulation on VSMCs. An AD murine model was constructed and clinical evaluation was performed to explore the critical roles of miR-564 in vivo. At the same time, the level of inflammation was detected using quantitative real-time PCR and immunofluorescence.
Results
Overexpression of miR-564 inhibited cell proliferation and migration, as well as phenotype switch, with or without platelet-derived growth factor BB (PDGF-BB) treatment, whereas downregulation of miR-564 led to opposite results. Mechanistically, miR-564 directly interacted with the target genes proto-oncogene (SKI) and neurogranin (NRGN) to regulate the biological functions of VSMCs. In particular, animal experiments demonstrated that miR-564 can alleviate the progression of AD mainly through mediating phenotypic swithing and inflammation which was consistent with clinical evaluation.
Conclusions
Our study identified miR-564 as a significant molecule that attenuates AD progression by inhibiting inflammation and VSMCs proliferation, migration and phenotypic transformation, suggesting that it may be a potential therapeutic target for AD.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 18 Jun 2022; 170:100-114
Li M, Yang Y, Zong J, Wang Z, ... Wang JX, Yu T
J Mol Cell Cardiol: 18 Jun 2022; 170:100-114 | PMID: 35728350
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Abstract

mA methyltransferase METTL3 participated in sympathetic neural remodeling post-MI via the TRAF6/NF-κB pathway and ROS production.

Qi L, Wang Y, Hu H, Li P, ... Li X, Yan S
Objective
Sudden cardiac death caused by ventricular arrhythmias (VAs) is the main cause of high mortality in patients with myocardial infarction (MI). Sympathetic neural remodeling caused by inflammation after MI is closely associated with the occurrence of VAs. METTL3, the earliest identified m6A methyltransferase, is critical in mediating inflammatory responses. Our aim was to investigate whether the m6A methyltransferase METTL3 was involved in sympathetic remodeling post-MI and its specific mechanism.
Methods and results
A rat MI model was established via left coronary artery ligation. The expression of METTL3, TRAF6, NOX2, and NF-κB increased at 3 days and remained elevated at 7 days after MI, as determined via Western blotting. METTL3 was primarily present in macrophages, as determined via immunofluorescence. Intramyocardial injection of lentivirus carrying METTL3-shRNA inhibited METTL3 expression in vivo. Methylated immunoprecipitation-qPCR determined the METTL3 knockdown inhibited the m6A level of TRAF6 mRNA 3\'-UTR. The co-immunoprecipitation experiment proved that METTL3 combines with TRAF6. Western blotting showed that silencing METTL3 inhibited TRAF6 level, NF-κB activation, and ROS production; decreased cytokine release (TNF-α and IL-1β); and downregulated nerve growth factor expression. Finally, METTL3 knockdown reduced sympathetic remodeling after MI, as determined via immunofluorescence assays of tyrosine hydroxylase and growth-associated protein 43. Programmed electrical stimulation, renal sympathetic nerve activity recording, and haemodynamic measurements showed that METTL3 inhibition decreased sympathetic activity and improved cardiac function.
Conclusions
Downregulation of METTL3 expression attenuated the excessive sympathetic neural remodeling induced by MI, further reducing the incidence of VAs and improving cardiac function. This was partly associated with the inhibition of the TRAF6/NF-κB pathway and ROS production.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 16 Jun 2022; 170:87-99
Qi L, Wang Y, Hu H, Li P, ... Li X, Yan S
J Mol Cell Cardiol: 16 Jun 2022; 170:87-99 | PMID: 35717715
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Abstract

ICAM-1-related noncoding RNA accelerates atherosclerosis by amplifying NF-κB signaling.

Ding S, Liu J, Han X, Ding W, ... Tian XL, Cao H
Long noncoding RNAs (lncRNAs) are critical regulators of inflammation with great potential as new therapeutic targets. However, the role of lncRNAs in early atherosclerosis remains poorly characterized. This study aimed to identify the key lncRNA players in activated endothelial cells (ECs). The lncRNAs in response to pro-inflammatory factors in ECs were screened through RNA sequencing. ICAM-1-related non-coding RNA (ICR) was identified as the most potential candidate for early atherosclerosis. ICR is essential for intercellular adhesion molecule-1 (ICAM1) expression, EC adhesion and migration. In a high fat diet-induced atherosclerosis model in mice, ICR is upregulated in the development of atherosclerosis. After intravenous injection of adenovirus carrying shRNA for mouse ICR, the atherosclerotic plaque area was markedly reduced with the declined expression of ICR and ICAM1. Mechanistically, ICR stabilized the mRNA of ICAM1 in quiescent ECs; while under inflammatory stress, ICR upregulated ICAM1 in a nuclear factor kappa B (NF-κB) dependent manner. RNA-seq analysis showed pro-inflammatory targets of NF-κB were regulated by ICR. Furthermore, the chromatin immunoprecipitation assays showed that p65 binds to ICR promoter and facilitates its transcription. Interestingly, ICR, in turn, promotes p65 accumulation and activity, forming a positive feedback loop to amplify NF-κB signaling. Preventing the degradation of p65 using proteasome inhibitors rescued the expression of NF-κB targets suppressed by ICR. Taken together, ICR acts as an accelerator to amplify NF-κB signaling in activated ECs and suppressing ICR is a promising early intervention for atherosclerosis through ICR/p65 loop blockade.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 14 Jun 2022; 170:75-86
Ding S, Liu J, Han X, Ding W, ... Tian XL, Cao H
J Mol Cell Cardiol: 14 Jun 2022; 170:75-86 | PMID: 35714558
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Abstract

Deficiency of proline/serine-rich coiled-coil protein 1 (PSRC1) accelerates trimethylamine N-oxide-induced atherosclerosis in ApoE mice.

Luo T, Liu D, Guo Z, Chen P, ... Ou C, Chen M
Aims
The main therapeutic strategies for coronary artery disease (CAD) are mainly based on the correction of abnormal cholesterol levels; however, residual risks remain. The newly proven gut microbial metabolite trimethylamine N-oxide (TMAO) linked with CAD has broadened our horizons. In this study, we determined the role of proline/serine-rich coiled-coil protein 1 (PSRC1) in TMAO-driven atherosclerosis.
Methods and results
We first analyzed the levels of TMAO and PSRC1 in patients with or without atherosclerosis with a target LDL-C < 1.8 mmol/L. Plasma TMAO levels were increased and negatively associated with decreased PSRC1 in peripheral blood mononuclear cells. Animals and in vitro studies showed that TMAO inhibited macrophage PSRC1 expression due to DNA hypermethylation of CpG islands. ApoE-/- mice fed a choline-supplemented diet exhibited reduced PSRC1 expression accompanied by increased atherosclerotic lesions and plasma TMAO levels. We further deleted PSRC1 in apoE-/- mice and PSRC1 deficiency significantly accelerated choline-induced atherogenesis, characterized by increased macrophage infiltration, foam cell formation and M1 macrophage polarization. Mechanistically, we overexpressed and knocked out PSRC1 in cultured macrophages to explore the mechanisms underlying TMAO-induced cholesterol accumulation and inflammation. PSRC1 deletion impaired reverse cholesterol transport and enhanced cholesterol uptake and inflammation, while PSRC1 overexpression rescued the proatherogenic phenotype observed in TMAO-stimulated macrophages, which was partially attributed to sulfotransferase 2B1b (SULT2B1b) inhibition.
Conclusions
Herein, clinical data provide evidence that TMAO may participate in the development of CAD beyond well-controlled LDL-C levels. Our work also suggests that PSRC1 is a negative regulator mediating the unfavorable effects of TMAO-containing diets. Therefore, PSRC1 overexpression and reduced choline consumption may further alleviate atherosclerosis.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 08 Jun 2022; 170:60-74
Luo T, Liu D, Guo Z, Chen P, ... Ou C, Chen M
J Mol Cell Cardiol: 08 Jun 2022; 170:60-74 | PMID: 35690006
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Abstract

Nuclear receptor Nur77 protects against oxidative stress by maintaining mitochondrial homeostasis via regulating mitochondrial fission and mitophagy in smooth muscle cell.

Geng N, Chen T, Chen L, Zhang H, ... Tao Z, Shao Q
Angiotensin II (AngII) induces disruption of mitochondrial homeostasis and oxidative stress. Nuclear receptor NR4A1 (Nur77) plays an important role in vascular smooth muscle cells (VSMCs) function. However, the role of Nur77 in AngII-induced mitochondrial dynamics and oxidative stress in VSMCs remains unknown. In an in vitro model of AngII-treated cells, we discovered that Nur77 knockout aggravated AngII-induced oxidative stress in VSMCs, whereas activation of Nur77 by celastrol diminished them. Concomitantly, disturbance of mitochondrial dynamics induced by AngII was further exacerbated in Nur77 deficient VSMCs compared to wild-type (WT) VSMCs. Interestingly, Nur77 deletion increased mitochondrial fission but not fusion as evidenced by upregulated fission related genes (Fis1 and Drp1) but not fusion (Opa1 and Mfn2) under AngII stimulation in VSMCs. Mechanically, Nur77 could directly bind to the promoter regions of Fis1 and Drp1 and repress their transcription. Furthermore, we observed that Nur77 additionally promoted mitochondrial homeostasis by increasing mitophagic flux in a transcription-independent manner upon AngII challenge. By using an in vivo model of AngII-induced abdominal aortic aneurysm (AAA), we finally validated the protective role of Nur77 involved in the mitochondrial fission process and mitophagic flux in aortas, which was correlated with the occurrence and development of AAA in AngII-infused mice. Our data defines an essential role of Nur77 in regulating oxidative stress by maintaining mitochondrial homeostasis in VSMCs via both transcription-dependent and transcription-independent manner, supporting the therapeutic potential of Nur77 targeting in vascular diseases.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 02 Jun 2022; 170:22-33
Geng N, Chen T, Chen L, Zhang H, ... Tao Z, Shao Q
J Mol Cell Cardiol: 02 Jun 2022; 170:22-33 | PMID: 35661620
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Abstract

Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias and disrupts the fine-tuning of G signaling.

Dahlen SA, Bernadyn TF, Dixon AJ, Sun B, ... Owens EA, Osei-Owusu P
Aims
Cardiac contractility, essential to maintaining proper cardiac output and circulation, is regulated by G protein-coupled receptor (GPCR) signaling. Previously, the absence of regulator of G protein signaling (RGS) 2 and 5, separately, was shown to cause G protein dysregulation, contributing to modest blood pressure elevation and exaggerated cardiac hypertrophic response to pressure-overload. Whether RGS2 and 5 redundantly control G protein signaling to maintain cardiovascular homeostasis is unknown. Here we examined how the dual absence of RGS2 and 5 (Rgs2/5 dbKO) affects blood pressure and cardiac structure and function.
Methods and results
We found that Rgs2/5 dbKO mice showed left ventricular dilatation at baseline by echocardiography. Cardiac contractile response to dobutamine stress test was sex-dependently reduced in male Rgs2/5 dbKO relative to WT mice. When subjected to surgery-induced stress, male Rgs2/5 dbKO mice had 75% mortality within 72-96 h after surgery, accompanied by elevated baseline blood pressure and decreased cardiac contractile function. At the cellular level, cardiomyocytes (CM) from Rgs2/5 dbKO mice showed augmented Ca2+ transients and increased incidence of arrhythmia without augmented contractile response to electrical field stimulation (EFS) and activation of β-adrenergic receptors (βAR) with isoproterenol. Dual loss of Rgs2 and 5 suppressed forskolin-induced cAMP production, which was restored by Gi/o inactivation with pertussis toxin that also reduced arrhythmogenesis during EFS or βAR stimulation. Cardiomyocyte NCX and PMCA mRNA expression was unaffected in Rgs2/5 dbKO male mice. However, there was an exaggerated elevation of EFS-induced cytoplasmic Ca2+ in the presence of SERCA blockade with thapsigargin.
Conclusions
We conclude that RGS2 and 5 promote normal ventricular rhythm by coordinating their regulatory activity towards Gi/o signaling and facilitating cardiomyocyte calcium handling.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 02 Jun 2022; 170:34-46
Dahlen SA, Bernadyn TF, Dixon AJ, Sun B, ... Owens EA, Osei-Owusu P
J Mol Cell Cardiol: 02 Jun 2022; 170:34-46 | PMID: 35661621
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Abstract

Turning back the clock: A concise viewpoint of cardiomyocyte cell cycle activation for myocardial regeneration and repair.

Zhu W, Sun J, Bishop SP, Sadek H, Zhang J
Patients with acute myocardial infarction (MI) could progress to end-stage congestive heart failure, which is one of the most significant problems in public health. From the molecular and cellular perspective, heart failure often results from the loss of cardiomyocytes-the fundamental contractile unit of the heart-and the damage caused by myocardial injury in adult mammals cannot be repaired, in part because mammalian cardiomyocytes undergo cell-cycle arrest during the early perinatal period. However, recent studies in the hearts of neonatal small and large mammals suggest that the onset of cardiomyocyte cell-cycle arrest can be reversed, which may lead to the development of entirely new strategies for the treatment of heart failure. In this Viewpoint, we summarize these and other provocative findings about the cellular and molecular mechanisms that regulate cardiomyocyte proliferation and how they may be targeted to turn back the clock of cardiomyocyte cell-cycle arrest and improve recovery from cardiac injury and disease.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 01 Jun 2022; 170:15-21
Zhu W, Sun J, Bishop SP, Sadek H, Zhang J
J Mol Cell Cardiol: 01 Jun 2022; 170:15-21 | PMID: 35660800
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Abstract

DEC1 represses cardiomyocyte hypertrophy by recruiting PRP19 as an E3 ligase to promote ubiquitination-proteasome-mediated degradation of GATA4.

Cheng L, Xu C, Chen Y, Li J, ... Wei X, Fang J
Although the pro-hypertrophic role of GATA binding protein 4 (GATA4) during cardiac hypertrophy has been well established, the negative regulatory mechanism to counteract its hyperactivation remains elusive. We hypothesized that the hyperactivation of GATA4 could be a result of loss of interaction between GATA4 with specific suppressors. Using high throughput mass spectrometry technology, we carried out a proteomic screen for endogenous suppressor of GATA4, which disassociated with GATA4 during the hypertrophic response in a cultured cardiac myoblast cell line (H9C2 cells). We identified differentiated embryo chondrocyte 1 (DEC1) negatively regulated the function of GATA4 through physical interaction and negatively regulated cardiac hypertrophy both in vivo and in vitro. Particularly, DEC1 promoted the ubiquitination and proteasome-mediated degradation of GATA4, but did not function as an E3 ligase. Again, using mass spectrometry technology, we systematically identified pre-mRNA processing factor 19 (PRP19) as a newfound E3 ligase, which promoted the K6-linked ubiquitination of GATA4 at its lysine 256. Functional experiments performed in cultured neonatal rat ventricular myocytes and H9C2 cells demonstrated that both DEC1 and PRP19 negatively regulated agonist-induced cardiomyocyte hypertrophic responses. Furthermore, rescue experiments performed in these cells revealed that DEC1 and PRP19 suppressed cardiomyocyte hypertrophy by inhibiting the function of GATA4. Our study thus defined the novel DEC1-PRP19-GATA4 axis to be a previously unknown mechanism in regulating cardiomyocyte hypertrophy. Although GATA4 is indispensable for normal cardiac function, harnessing DEC1- or PRP19-mediated negative regulation to counteract the hyperactivation of GATA4 might serve as a novel therapeutic strategy for pathological cardiac hypertrophy.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 31 May 2022; 169:96-110
Cheng L, Xu C, Chen Y, Li J, ... Wei X, Fang J
J Mol Cell Cardiol: 31 May 2022; 169:96-110 | PMID: 35659652
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Abstract

Uptake-leak balance of SR Ca determines arrhythmogenic potential of RyR2 cardiomyocytes.

Lopez R, Janicek R, Fernandez-Tenorio M, Courtehoux M, ... Egger M, Niggli E
Mutations of the RyR2 are channelopathies that can predispose to life threatening catecholaminergic polymorphic ventricular tachycardias (CPVTs) during exercise or stress. However, the cellular and molecular mechanisms that are causal for the arrhythmias downstream of the β-adrenergic receptor (β-AR) activation are not defined. They may be specific and different for each particular RyR2 mutation. Obvious possibilities are the phosphorylation of the mutated RyR2s or the stimulation of the SR Ca2+ pump (SERCA), which could increase SR Ca2+ loading. Potentially arrhythmogenic Ca2+ signals, such as Ca2+ waves, were recorded and analyzed from WT and RyR2R420Q+/- mouse cardiomyocytes with confocal microscopy after field stimulation at 1 Hz. In RyR2R420Q+/- cardiomyocytes we found a higher occurrence and frequency of Ca2+ waves, particularly upon β-AR stimulation with isoproterenol. This was accompanied by a shorter latency to the first spontaneous wave. Wave velocity from raw traces, as well as amplitude and decay time constant (τ) analyzed in de-skewed traces were comparable in both cell types. To obtain further insight into the role of the SERCA we selectively stimulated SERCA in permeabilized myocytes using Fab fragments of a PLB antibody (2D12). Surprisingly, SERCA stimulation alone resulted in considerably higher wave frequencies than when mimicking β-AR stimulation with cAMP, particularly in RyR2R420Q+/- cardiomyocytes. This may be a consequence of some protective SR Ca2+ unloading resulting from the SR Ca2+ leak via phosphorylated RyR2s in cAMP. Spark-to-spark recovery analysis suggested a remarkably higher Ca2+ release sensitivity in RyR2R420Q+/- cells, both in control and upon β-AR stimulation. Together these findings suggest that the fine balance between SR Ca2+ loading via SERCA and the Ca2+ leak via mutated and phosphorylated RyR2s is an important determinant for the overall cellular arrhythmogenicity prevailing in the RyR2R420Q+/- myocytes.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 26 May 2022; epub ahead of print
Lopez R, Janicek R, Fernandez-Tenorio M, Courtehoux M, ... Egger M, Niggli E
J Mol Cell Cardiol: 26 May 2022; epub ahead of print | PMID: 35644481
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Abstract

Standardised method for cardiomyocyte isolation and purification from individual murine neonatal, infant, and adult hearts.

Nicks AM, Holman SR, Chan AY, Tsang M, ... Iismaa SE, Graham RM
Primary cardiomyocytes are invaluable for understanding postnatal heart development. However, a universal method to obtain freshly purified cardiomyocytes without using different age-dependent isolation procedures and cell culture, is lacking. Here, we report the development of a standardised method that allows rapid isolation and purification of high-quality cardiomyocytes from individual neonatal through to adult C57BL/6 J murine hearts. Langendorff retrograde perfusion, which is currently limited to adult hearts, was adapted for use in neonatal and infant hearts by developing an easier in situ aortic cannulation technique. Tissue digestion conditions were optimised to achieve efficient digestion of hearts of all ages in a comparable timeframe (<14 min). This resulted in a high yield (1.56-2.2 × 106 cells/heart) and viability (~70-100%) of cardiomyocytes post-isolation. An immunomagnetic cell separation step was then applied to yield highly purified cardiomyocytes (~95%) as confirmed by immunocytochemistry, flow cytometry, and qRT-PCR. For cell type-specific studies, cardiomyocyte DNA, RNA, and protein could be extracted in sufficient yields to conduct molecular experiments. We generated transcriptomic datasets for neonatal cardiomyocytes from individual hearts, for the first time, which revealed nine sex-specific genes (FDR < 0.05) encoded on the sex chromosomes. Finally, we also developed an in situ fixation protocol that preserved the native cytoarchitecture of cardiomyocytes (~94% rod-shaped post-isolation), and used it to evaluate cell morphology during cardiomyocyte maturation, as well as capture spindle-shaped neonatal cells undergoing cytokinesis. Together, these procedures allow molecular and morphological profiling of high-quality cardiomyocytes from individual hearts of any postnatal age.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 26 May 2022; epub ahead of print
Nicks AM, Holman SR, Chan AY, Tsang M, ... Iismaa SE, Graham RM
J Mol Cell Cardiol: 26 May 2022; epub ahead of print | PMID: 35644482
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Abstract

CXCR4 blockade in macrophage promotes angiogenesis in ischemic hindlimb by modulating autophagy.

Ma Q, Zhang N, You Y, Zhu J, ... Xie X, Yu H
Chemokine receptor CXCR4 plays a crucial role in leukocyte recruitment and inflammation regulation to influence tissue repair in ischemic diseases. Here we assessed the effect of CXCR4 expression in macrophages on angiogenesis in the ischemic hindlimb of a mouse. Inflammatory cells were increased in the ischemic muscles of hindlimb, and CXCR4 was highly expressed in the infiltrated macrophages but not in neutrophils. Myeloid-specific CXCR4 knockout attenuated macrophage infiltration and subsequent reduced inflammatory response in the ischemic hindlimb, accompanied with better blood reperfusion and higher capillary density as compared with that in LysM Cre+/- (Cre) mice. Similar outcomes were also observed in CRE mice whose bone marrow cells were replaced with those from CXCR4-deficient mice. Gene ontology cluster analysis reviewed that Decorin, a negative regulator of angiogenesis, was reduced in CXCR4-deficient macrophages. CXCR4-deficient macrophages were less inducible into M1 phase by lipopolysaccharide and more favorable for M2 polarization under oxygen/glucose deprivation condition. Enhanced autophagy was detected in CXCR4-deficient macrophages, which was associated with less expression of both Decorin and the inflammatory cytokines. In summary, myeloid-specific CXCR4 deficiency reduced monocyte infiltration and the secretion of inflammatory cytokines and Decorin from macrophages, thus blunting inflammation response and promoting angiogenesis in the ischemic hindlimb.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 18 May 2022; 169:57-70
Ma Q, Zhang N, You Y, Zhu J, ... Xie X, Yu H
J Mol Cell Cardiol: 18 May 2022; 169:57-70 | PMID: 35597127
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Abstract

Necroptosis in heart disease: Molecular mechanisms and therapeutic implications.

Guo X, Chen Y, Liu Q
Cell death is a crucial event underlying cardiac ischemic injury, pathological remodeling, and heart failure. Unlike apoptosis, necrosis had long been regarded as a passive and unregulated process. However, recent studies demonstrate that a significant subset of necrotic cell death is actively mediated through regulated pathways - a process known as \"regulated necrosis\". As a form of regulated necrosis, necroptosis is mediated by death receptors and executed through the activation of receptor interacting protein kinase 3 (RIPK3) and its downstream substrate mixed lineage kinase-like domain (MLKL). Recent studies have provided compelling evidence that necroptosis plays an important role in myocardial homeostasis, ischemic injury, pathological remodeling, and heart failure. Moreover, it has been shown that genetic and pharmacological manipulations of the necroptosis signaling pathway elicit cardioprotective effects. Important progress has also been made regarding the molecular mechanisms that regulate necroptotic cell death in vitro and in vivo. In this review, we discuss molecular and cellular mechanisms of necroptosis, potential crosstalk between necroptosis and other cell death pathways, functional implications of necroptosis in heart disease, and new therapeutic strategies that target necroptosis signaling.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 18 May 2022; epub ahead of print
Guo X, Chen Y, Liu Q
J Mol Cell Cardiol: 18 May 2022; epub ahead of print | PMID: 35597275
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Abstract

Matricellular proteins: Potential biomarkers and mechanistic factors in aortic aneurysms.

Li Z, Cong X, Kong W
Aortic aneurysms, including thoracic aortic aneurysms and abdominal aortic aneurysms, are life-threatening macrovascular diseases with high mortality. The already known key mechanisms implicated in aortic aneurysm pathogenesis involve the remodeling of the extracellular matrix and a set of cellular responses, such as inflammation, oxidative stress and vascular smooth muscle cell dysfunction. Matricellular proteins constitute a group of nonstructural extracellular proteins that link the interaction between cells and their extracellular microenvironment and have been widely reported in different diseases, including aortic aneurysms. In the present review, we summarize the role of various matricellular proteins in the pathogenesis and progression of aortic aneurysms, as well as address the possibility of using these proteins as biomarkers and pathogenic factors, to highlight their clinical significance in aortic aneurysms.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 13 May 2022; 169:41-56
Li Z, Cong X, Kong W
J Mol Cell Cardiol: 13 May 2022; 169:41-56 | PMID: 35576729
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Abstract

Advances in three-dimensional bioprinted stem cell-based tissue engineering for cardiovascular regeneration.

Khanna A, Ayan B, Undieh AA, Yang YP, Huang NF
Three-dimensional (3D) bioprinting of cellular or biological components are an emerging field to develop tissue structures that mimic the spatial, mechanochemical and temporal characteristics of cardiovascular tissues. 3D multi-cellular and multi-domain organotypic biological constructs can better recapitulate in vivo physiology and can be utilized in a variety of applications. Such applications include in vitro cellular studies, high-throughput drug screening, disease modeling, biocompatibility analysis, drug testing and regenerative medicine. A major challenge of 3D bioprinting strategies is the inability of matrix molecules to reconstitute the complexity of the extracellular matrix and the intrinsic cellular morphologies and functions. An important factor is the inclusion of a vascular network to facilitate oxygen and nutrient perfusion in scalable and patterned 3D bioprinted tissues to promote cell viability and functionality. In this review, we summarize the new generation of 3D bioprinting techniques, the kinds of bioinks and printing materials employed for 3D bioprinting, along with the current state-of-the-art in engineered cardiovascular tissue models. We also highlight the translational applications of 3D bioprinting in engineering the myocardium cardiac valves, and vascular grafts. Finally, we discuss current challenges and perspectives of designing effective 3D bioprinted constructs with native vasculature, architecture and functionality for clinical translation and cardiovascular regeneration.

Published by Elsevier Ltd.

J Mol Cell Cardiol: 12 May 2022; 169:13-27
Khanna A, Ayan B, Undieh AA, Yang YP, Huang NF
J Mol Cell Cardiol: 12 May 2022; 169:13-27 | PMID: 35569213
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Abstract

Regulation of extracellular matrix composition by fibroblasts during perinatal cardiac maturation.

Kuwabara JT, Hara A, Heckl JR, Peña B, ... Apte SS, Tallquist MD
Background
Cardiac fibroblasts are the main non-myocyte population responsible for extracellular matrix (ECM) production. During perinatal development, fibroblast expansion coincides with the transition from hyperplastic to hypertrophic myocardial growth. Therefore, we investigated the consequences of fibroblast loss at the time of cardiomyocyte maturation by depleting fibroblasts in the perinatal mouse.
Methods and results
We evaluated the microenvironment of the perinatal heart in the absence of fibroblasts and the potential functional impact of fibroblast loss in regulation of cardiomyocyte cell cycle arrest and binucleation. Cre-mediated expression of diphtheria toxin A in PDGFRα expressing cells immediately after birth eliminated 70-80% of the cardiac fibroblasts. At postnatal day 5, hearts lacking fibroblasts appeared similar to controls with normal morphology and comparable numbers of endothelial and smooth muscle cells, despite a pronounced reduction in fibrillar collagen. Immunoblotting and proteomic analysis of control and fibroblast-deficient hearts identified differential abundance of several ECM proteins. In addition, fibroblast loss decreased tissue stiffness and resulted in increased cardiomyocyte mitotic index and DNA synthesis. Moreover, decellularized matrix from fibroblast-deficient hearts promoted cardiomyocyte DNA replication. While cardiac architecture was not overtly affected by fibroblast reduction, few pups survived past postnatal day 11, suggesting an overall requirement for PDGFRα expressing fibroblasts.
Conclusions
These studies demonstrate the key role of fibroblasts in matrix production and cardiomyocyte cross-talk during mouse perinatal heart maturation and revealed that fibroblast-derived ECM may modulate cardiomyocyte maturation in vivo. Neonatal depletion of fibroblasts demonstrated that although hearts can tolerate reduced ECM composition, fibroblast loss eventually leads to perinatal death as the approach simultaneously reduced fibroblast populations in other organs.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 12 May 2022; epub ahead of print
Kuwabara JT, Hara A, Heckl JR, Peña B, ... Apte SS, Tallquist MD
J Mol Cell Cardiol: 12 May 2022; epub ahead of print | PMID: 35569524
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Abstract

Partial and complete loss of myosin binding protein H-like cause cardiac conduction defects.

Barefield DY, Yamakawa S, Tahtah I, Sell JJ, ... Fishman GI, McNally EM
A premature truncation of MYBPHL in humans and a loss of Mybphl in mice is associated with dilated cardiomyopathy, atrial and ventricular arrhythmias, and atrial enlargement. MYBPHL encodes myosin binding protein H-like (MyBP-HL). Prior work in mice indirectly identified Mybphl expression in the atria and in small puncta throughout the ventricle. Because of its genetic association with human and mouse cardiac conduction system disease, we evaluated the anatomical localization of MyBP-HL and the consequences of loss of MyBP-HL on conduction system function. Immunofluorescence microscopy of normal adult mouse ventricles identified MyBP-HL-positive ventricular cardiomyocytes that co-localized with the ventricular conduction system marker contactin-2 near the atrioventricular node and in a subset of Purkinje fibers. Mybphl heterozygous ventricles had a marked reduction of MyBP-HL-positive cells compared to controls. Lightsheet microscopy of normal perinatal day 5 mouse hearts showed enrichment of MyBP-HL-positive cells within and immediately adjacent to the contactin-2-positive ventricular conduction system, but this association was not apparent in Mybphl heterozygous hearts. Surface telemetry of Mybphl-null mice revealed atrioventricular block and atrial bigeminy, while intracardiac pacing revealed a shorter atrial relative refractory period and atrial tachycardia. Calcium transient analysis of isolated Mybphl-null atrial cardiomyocytes demonstrated an increased heterogeneity of calcium release and faster rates of calcium release compared to wild type controls. Super-resolution microscopy of Mybphl heterozygous and homozygous null atrial cardiomyocytes showed ryanodine receptor disorganization compared to wild type controls. Abnormal calcium release, shorter atrial refractory period, and atrial dilation seen in Mybphl null, but not wild type control hearts, agree with the observed atrial arrhythmias, bigeminy, and atrial tachycardia, whereas the proximity of MyBP-HL-positive cells with the ventricular conduction system provides insight into how a predominantly atrial expressed gene contributes to ventricular arrhythmias and ventricular dysfunction.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 06 May 2022; epub ahead of print
Barefield DY, Yamakawa S, Tahtah I, Sell JJ, ... Fishman GI, McNally EM
J Mol Cell Cardiol: 06 May 2022; epub ahead of print | PMID: 35533732
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Abstract

The cell-autonomous and non-cell-autonomous roles of the Hippo pathway in heart regeneration.

Liu S, Li RG, Martin JF
Cardiomyocytes are differentiated heart muscle cells with minimal self-renewal ability. Thus, loss of cardiomyocytes from cardiovascular disease and injury cannot be effectively replenished. Recent studies in animal models have indicated that induction of endogenous cardiomyocyte proliferation is essential for cardiac renewal and that inhibiting the Hippo signaling pathway can stimulate cardiomyocyte proliferation and heart regeneration. Increasing evidence has suggested that cardiomyocyte proliferation requires a permissive microenvironment that consists of multiple cell types. In this review, we summarize recent studies that highlight how the Hippo pathway regulates heart regeneration through cell-autonomous and non-cell-autonomous mechanisms. We also discuss recent translational studies in large animal models that demonstrate the therapeutic potential of targeting the Hippo pathway in the treatment of heart disease.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 05 May 2022; 168:98-106
Liu S, Li RG, Martin JF
J Mol Cell Cardiol: 05 May 2022; 168:98-106 | PMID: 35526477
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Abstract

Minimally invasive delivery of a hydrogel-based exosome patch to prevent heart failure.

Cheng G, Zhu D, Huang K, Caranasos TG
Coronary heart disease (CHD) has been the number one killer in the United States for decades and causes millions of deaths each year. Clinical treatment of heart ischemic injury relieves symptoms in the acute stage of CHD; however, patients with an infarcted heart muscle can develop heart failure (HF) due to chronic maladaptive remodeling. Regenerative therapy has been studied as a potential treatment option for myocardial infarction (MI) and HF. Cardiac patches have been designed and tested to increase therapeutic retention and integration in this field. However, the delivery usually requires invasive surgical techniques, including open-chest surgeries and heart or pericardium manipulation. Those procedures may cause chronic adhesions between the heart anterior wall and chest wall. This study created and tested an injectable ExoGel by embedding mesenchymal stem cell (MSC) -derived exosomes into hyaluronic acid (HA) hydrogel. ExoGel was injected into the pericardial cavity of rats with transverse aortic constriction (TAC) induced heart failure. ExoGel therapy reduced LV chamber size and preserved wall thickness. The feasibility and safety ExoGel injection was further confirmed in a pig model.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 03 May 2022; epub ahead of print
Cheng G, Zhu D, Huang K, Caranasos TG
J Mol Cell Cardiol: 03 May 2022; epub ahead of print | PMID: 35523270
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Abstract

PPAR-δ: A key nuclear receptor in vascular function and remodeling.

Xiao L, Wang N
Vascular function is critical for the maintenance of body\'s homeostasis and is tightly regulated by complex interactions among the vessel wall, hemodynamics, neuro-endocrine factors and metabolic alteration. A variety of cardiovascular risks instigate pro-inflammatory and oxidative responses to impair vascular function, leading to pathological vascular remodeling. Peroxisome proliferator-activated receptor-δ (PPAR-δ) is a ligand-activated nuclear receptor and transcription factor that regulates cell growth and differentiation, metabolism and wound healing. Being expressed in vascular endothelial cells, smooth muscle cells and monocytes, PPAR-δ has pleotropic effects in vascular biology and pathology. In this review, we discussed recent advances regarding the functional roles of PPAR-δ as a critical regulator of vascular homeostasis and as a potential target for the intervention of cardiovascular diseases.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 28 Apr 2022; epub ahead of print
Xiao L, Wang N
J Mol Cell Cardiol: 28 Apr 2022; epub ahead of print | PMID: 35490844
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Abstract

Time series RNA-seq analysis identifies MAPK10 as a critical gene in diabetes mellitus-induced atrial fibrillation in mice.

Liu F, Deng Y, Zhao Y, Li Z, ... Liu Y, Xia Y
Atrial fibrillation (AF) is a major complication of type 2 diabetes mellitus (T2DM) and plays critical roles in the pathogenesis of atrial remodeling. However, the differentially expressed genes in atria during the development of AF induced by hyperglycemia have rarely been reported. Here, we showed time-dependent increased AF incidence and duration, atrial enlargement, inflammation, fibrosis, conduction time and action potential duration in db/db mice, a model of T2DM. RNA sequencing analysis showed that 2256 genes were differentially expressed in the atria at 12, 14 and 16 weeks. Gene Ontology analysis showed that these genes participate primarily in cell adhesion, cellular response to interferon-beta, immune system process, positive regulation of cell migration, ion transport and cellular response to interferon-gamma. Analysis of significant pathways revealed the IL-17 signaling pathway, TNF signaling pathway, MAPK signaling pathway, chemokine signaling pathway, and cAMP receptor signaling. Additionally, these differentially expressed genes were classified into 50 profiles by hierarchical clustering analysis. Twelve of these profiles were significant and comprised 1115 genes. Gene coexpression network analysis identified that mitogen-activated protein kinase 10 (MAPK10) was localized in the core of the gene network and was the most highly expressed gene at different time points. Knockdown of MAPK10 markedly attenuated DM-induced AF incidence, atrial inflammation, fibrosis, electrical disorder and apoptosis in db/db mice. In summary, the present findings revealed that many genes are involved in DM-induced AF and that MAPK10 plays a central role in this disease, indicating that strategies targeting MAPK10 may represent a potential therapeutic approach to treat DM-induced AF.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 27 Apr 2022; epub ahead of print
Liu F, Deng Y, Zhao Y, Li Z, ... Liu Y, Xia Y
J Mol Cell Cardiol: 27 Apr 2022; epub ahead of print | PMID: 35489387
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Abstract

E-cigarette exposure with or without heating the e-liquid induces differential remodeling in the lungs and right heart of mice.

Getiye Y, Peterson MR, Phillips BD, Carrillo D, Bisha B, He G
Various cardiopulmonary pathologies associated with electronic cigarette (EC) vaping have been reported. This study investigated the differential adverse effects of heating-associated by-products versus the intact components of EC aerosol to the lungs and heart of mice. We further dissected the roles of caspase recruitment domain-containing protein 9 (CARD9)-associated innate immune response and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in EC exposure-induced cardiopulmonary injury. C57BL/6 wild type (WT), CARD9-/-, and NLRP3-/- mice were exposed to EC aerosol 3 h/day, 5 days/week for 6 month with or without heating the e-liquid with exposure to ambient air as the control. In WT mice, EC exposure with heating (EwH) significantly increased right ventricle (RV) free wall thickness at systole and diastole. However, EC exposure without heating (EwoH) caused a significant decrease in the wall thickness at systole. RV fractional shortening was also markedly reduced following EwH in WT and NLRP3-/- mice. Further, EwH activated NF-κB and p38 MAPK inflammatory signaling in the lungs, but not in the RV, in a CARD9- and NLRP3-dependent manner. Levels of circulatory inflammatory mediators were also elevated following EwH, indicating systemic inflammation. Moreover, EwoH activated TGF-β1/SMAD2/3/α-SMA fibrosis signaling in the lungs but not the RV of WT mice. In conclusion, EC aerosol exposure following EwH or EwoH induced differential cardiopulmonary remodeling and CARD9 innate immune and NLRP3 inflammasome contributed to the adverse effects.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 27 Apr 2022; epub ahead of print
Getiye Y, Peterson MR, Phillips BD, Carrillo D, Bisha B, He G
J Mol Cell Cardiol: 27 Apr 2022; epub ahead of print | PMID: 35489388
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Abstract

The effects of xeno-free cryopreservation on the contractile properties of human iPSC derived cardiomyocytes.

Chirikian O, Feinstein S, Faynus MA, Kim AA, ... Wu JC, Pruitt BL
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have advanced our ability to study the basic function of the heart and model cardiac diseases. Due to the complexities in stem cell culture and differentiation protocols, many researchers source their hiPSC-CMs from collaborators or commercial biobanks. Generally, the field has assumed the health of frozen cardiomyocytes is unchanged if the cells adhere to the substrate and commence beating. However, very few have investigated the effects of cryopreservation on hiPSC-CM\'s functional and transcriptional health at the cellular and molecular level. Here we review methods and challenges associated with cryopreservation, and examine the effects of cryopreservation on the functionality (contractility and calcium handling) and transcriptome of hiPSC-CMs from six healthy stem cell lines. Utilizing protein patterning methods to template physiological cell aspect ratios (7:1, length:width) in conjunction with polyacrylamide (PA) hydrogels, we measured changes in force generation and calcium handling of single hiPSC-CMs. We observed that cryopreservation altered the functionality and transcriptome of hiPSC-CMs towards larger sizes and contractile force as assessed by increased spread area and volume, single cell traction force microscopy and delayed calcium dynamics. hiPSC-CMs are broadly used for basic science research, regenerative medicine, and testing biological therapeutics. This study informs the design of experiments utilizing hiPSC-CMs to avoid confounding functional changes due to cryopreservation with other treatments.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 21 Apr 2022; epub ahead of print
Chirikian O, Feinstein S, Faynus MA, Kim AA, ... Wu JC, Pruitt BL
J Mol Cell Cardiol: 21 Apr 2022; epub ahead of print | PMID: 35461823
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Abstract

Targeting endothelial dysfunction and inflammation.

Wang L, Cheng CK, Yi M, Lui KO, Huang Y
Vascular endothelium maintains vascular homeostasis through liberating a spectrum of vasoactive molecules, both protective and harmful regulators of vascular tone, structural remodeling, inflammation and atherogenesis. An intricate balance between endothelium-derived relaxing factors (nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor) and endothelium-derived contracting factors (superoxide anion, endothelin-1 and constrictive prostaglandins) tightly regulates vascular function. Disruption of such balance signifies endothelial dysfunction, a critical contributor in aging and chronic cardiometabolic disorders, such as obesity, diabetes, hypertension, dyslipidemia and atherosclerotic vascular diseases. Among many proposed cellular and molecular mechanisms causing endothelial dysfunction, oxidative stress and inflammation are often the pivotal players and they are naturally considered as useful targets for intervention in patients with cardiovascular and metabolic diseases. In this article, we provide a recent update on the therapeutic values of pharmacological agents, such as cyclooxygenase-2 inhibitors, renin-angiotensin-system inhibitors, bone morphogenic protein 4 inhibitors, peroxisome proliferator-activated receptor δ agonists, and glucagon-like peptide 1-elevating drugs, and the physiological factors, particularly hemodynamic forces, that improve endothelial function by targeting endothelial oxidative stress and inflammation.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 20 Apr 2022; epub ahead of print
Wang L, Cheng CK, Yi M, Lui KO, Huang Y
J Mol Cell Cardiol: 20 Apr 2022; epub ahead of print | PMID: 35460762
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Abstract

Obscurin regulates ankyrin macromolecular complex formation.

Subramaniam J, Yamankurt G, Cunha SR
Obscurin is a large scaffolding protein in striated muscle that maintains sarcolemmal integrity and aligns the sarcoplasmic reticulum with the underlying contractile machinery. Ankyrins are a family of adaptor proteins with some isoforms that interact with obscurin. Previous studies have examined obscurin interacting with individual ankyrins. In this study, we demonstrate that two different ankyrins interact with obscurin\'s carboxyl terminus via independent ankyrin-binding domains (ABDs). Using in-vitro binding assays, co-precipitation assays, and FLIM-FRET analysis, we show that obscurin interacts with small ankyrin 1.5 (sAnk1.5) and the muscle-specific ankyrin-G isoform (AnkG107). While there is no direct interaction between sAnk1.5 and AnkG107, obscurin connects the two ankyrins both in vitro and in cells. Moreover, AnkG107 recruits β-spectrin to this macromolecular protein complex and mutating obscurin\'s ABDs disrupts complex formation. To further characterize AnkG107 interaction with obscurin, we measure obscurin-binding to different AnkG107 isoforms expressed in the heart and find that the first obscurin-binding domain in AnkG107 principally mediates this interaction. We also find that AnkG107 does not bind to filamin-C and displays minimal binding to plectin-1 compared to obscurin. Finally, both sAnk1.5-GFP and AnkG107-CTD-RFP are targeted to the M-lines of ventricular cardiomyocytes and mutating their obscurin-binding domains disrupts the M-line localization of these ankyrin constructs. Altogether, these findings support a model in which obscurin can interact via independent binding domains with two different ankyrin protein complexes to target them to the sarcomeric M-line of ventricular cardiomyocytes.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 18 Apr 2022; epub ahead of print
Subramaniam J, Yamankurt G, Cunha SR
J Mol Cell Cardiol: 18 Apr 2022; epub ahead of print | PMID: 35447147
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Abstract

Methods of mouse cardiomyocyte isolation from postnatal heart.

Feng J, Li Y, Nie Y
Primary cardiomyocytes (CMs) are invaluable materials used to study in vitro cardiac physiology and pathophysiology. However, there is still a lack of comprehensive, systematic and comparative studies on methods for isolation of primary CMs from postnatal hearts. Here, we aimed to compare and optimize protocols for the isolation of CMs from embryonic to adult stages. We found that the trypsin digestion method was suitable for embryonic mouse CM isolation. The Gentle MACS method yielded high- quality CMs from neonatal hearts (postnatal day 1- day 3, P1-P3). The Langendorff-free perfusion method was applicable for isolation of CMs from mice older than P3. P14 and P56 CMs could also be isolated by the Langendorff perfusion system. The transcriptional profiles and cellular function of the isolated CMs were respectively confirmed by RNA sequencing and Angiotensin II treatment, suggesting the feasibility and effectiveness of the isolation methods. Overall, this study supplies a series of detailed and optimized protocols to isolate CMs at different developmental stages, which provides support for the study of the mechanisms, pathology, and pharmacology of cardiovascular diseases.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 13 Apr 2022; epub ahead of print
Feng J, Li Y, Nie Y
J Mol Cell Cardiol: 13 Apr 2022; epub ahead of print | PMID: 35429553
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Abstract

Cardiovascular disease and the biology of aging.

Moturi S, Ghosh-Choudhary SK, Finkel T
The incidence and prevalence of a wide range of cardiovascular diseases increases as a function of age. This well-established epidemiological relationship suggests that chronological aging might contribute or increase susceptibility to varied conditions such as atherosclerosis, vascular stiffening or heart failure. Here, we explore the mechanistic links that connect both rare and common cardiovascular conditions to the basic biology of aging. These links provide a rational basis to begin to develop a new set of therapeutics targeting the fundamental mechanisms underlying the aging process and suggest that in the near future, age itself might become a modifiable cardiovascular risk factor.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 11 Apr 2022; 167:109-117
Moturi S, Ghosh-Choudhary SK, Finkel T
J Mol Cell Cardiol: 11 Apr 2022; 167:109-117 | PMID: 35421400
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Abstract

Preserved cardiac performance and adrenergic response in a rabbit model with decreased ryanodine receptor 2 expression.

Zheng J, Dooge HC, Pérez-Hernández M, Zhao YT, ... Valdivia HH, Alvarado FJ
Ryanodine receptor 2 (RyR2) is an ion channel in the heart responsible for releasing into the cytosol most of the Ca2+ required for contraction. Proper regulation of RyR2 is critical, as highlighted by the association between channel dysfunction and cardiac arrhythmia. Lower RyR2 expression is also observed in some forms of heart disease; however, there is limited information on the impact of this change on excitation-contraction (e-c) coupling, Ca2+-dependent arrhythmias, and cardiac performance. We used a constitutive knock-out of RyR2 in rabbits (RyR2-KO) to assess the extent to which a stable decrease in RyR2 expression modulates Ca2+ handling in the heart. We found that homozygous knock-out of RyR2 in rabbits is embryonic lethal. Remarkably, heterozygotes (KO+/-) show ~50% loss of RyR2 protein without developing an overt phenotype at the intact animal and whole heart levels. Instead, we found that KO+/- myocytes show (1) remodeling of RyR2 clusters, favoring smaller groups in which channels are more densely arranged; (2) lower Ca2+ spark frequency and amplitude; (3) slower rate of Ca2+ release and mild but significant desynchronization of the Ca2+ transient; and (4) a significant decrease in the basal phosphorylation of S2031, likely due to increased association between RyR2 and PP2A. Our data show that RyR2 deficiency, although remarkable at the molecular and subcellular level, has only a modest impact on global Ca2+ release and is fully compensated at the whole-heart level. This highlights the redundancy of RyR2 protein expression and the plasticity of the e-c coupling apparatus.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 09 Apr 2022; epub ahead of print
Zheng J, Dooge HC, Pérez-Hernández M, Zhao YT, ... Valdivia HH, Alvarado FJ
J Mol Cell Cardiol: 09 Apr 2022; epub ahead of print | PMID: 35413295
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Abstract

Synergistic FRET assays for drug discovery targeting RyR2 channels.

Rebbeck R, Ginsburg KS, Ko CY, Fasoli A, ... Bers DM, Cornea RL
A key therapeutic target for heart failure and arrhythmia is the deleterious leak through sarcoplasmic reticulum (SR) ryanodine receptor 2 (RyR2) calcium release channels. We have previously developed methods to detect the pathologically leaky state of RyR2 in adult cardiomyocytes by monitoring RyR2 binding to either calmodulin (CaM) or a biosensor peptide (DPc10). Here, we test whether these complementary binding measurements are effective as high-throughput screening (HTS) assays to discover small molecules that target leaky RyR2. Using FRET, we developed and validated HTS procedures under conditions that mimic a pathological state, to screen the library of 1280 pharmaceutically active compounds (LOPAC) for modulators of RyR2 in cardiac SR membrane preparations. Complementary FRET assays with acceptor-labeled CaM and DPc10 were used for Hit prioritization based on the opposing binding properties of CaM vs. DPc10. This approach narrowed the Hit list to one compound, Ro 90-7501, which altered FRET to suggest increased RyR2-CaM binding and decreased DPc10 binding. Follow-up studies revealed that Ro 90-7501 does not detrimentally affect myocyte Ca2+ transients. Moreover, Ro 90-7501 partially inhibits overall Ca2+ leak, as assessed by Ca2+ sparks in permeabilized rat cardiomyocytes. Together, these results demonstrate (1) the effectiveness of our HTS approach where two complementary assays synergize for Hit ranking and (2) a drug discovery process that combines high-throughput, high-precision in vitro structural assays with in situ myocyte assays of the pathologic RyR2 leak. These provide a drug discovery platform compatible with large-scale HTS campaigns, to identify agents that inhibit RyR2 for therapeutic development.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 09 Apr 2022; 168:13-23
Rebbeck R, Ginsburg KS, Ko CY, Fasoli A, ... Bers DM, Cornea RL
J Mol Cell Cardiol: 09 Apr 2022; 168:13-23 | PMID: 35405106
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Abstract

Transmural myocardial repair with engineered heart muscle in a rat model of heterotopic heart transplantation - A proof-of-concept study.

Jebran AF, Tiburcy M, Biermann D, Balfanz P, ... Kutschka I, Zimmermann WH
Engineered heart muscle (EHM) can be implanted epicardially to remuscularize the failing heart. In case of a severely scarred ventricle, excision of scar followed by transmural heart wall replacement may be a more desirable application. Accordingly, we tested the hypothesis that allograft (rat) and xenograft (human) EHM can also be administered as transmural heart wall replacement in a heterotopic, volume-loaded heart transplantation model. We first established a novel rat model model to test surgical transmural left heart wall repair. Subsequently and in continuation of our previous allograft studies, we tested outcome after implantation of contractile engineered heart muscle (EHM) and non-contractile engineered connective tissue (ECT) as well as engineered mesenchymal tissue (EMT) allografts as transmural heart wall replacement. Finally, proof-of-concept for the application of human EHM was obtained in an athymic nude rat model. Only in case of EHM implantation, remuscularization of the surgically created transmural defect was observed with palpable graft vascularization. Taken together, feasibility of transmural heart repair using bioengineered myocardial grafts could be demonstrated in a novel rat model of heterotopic heart transplantation.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 04 Apr 2022; 168:3-12
Jebran AF, Tiburcy M, Biermann D, Balfanz P, ... Kutschka I, Zimmermann WH
J Mol Cell Cardiol: 04 Apr 2022; 168:3-12 | PMID: 35390437
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Abstract

Cardio-oncology imaging tools at the translational interface.

Yaros K, Eksi B, Chandra A, Agusala K, Lehmann LH, Zaha VG
Cardiovascular imaging is an evolving component in the care of cancer patients. With improved survival following prompt cancer treatment, patients are facing increased risks of cardiovascular complications. While currently established imaging modalities are providing useful structural mechanical information, they continue to develop towards increased specificity. New modalities, emerging from basic science and oncology, are being translated, targeting earlier stages of cardiovascular disease. Besides these technical advances, matching an imaging modality with the patients\' individual risk level for a specific pathological change is part of a successful imaging strategy. The choice of suitable imaging modalities and time points for specific patients will impact the cardio-oncological risk stratification during surveillance and follow-up monitoring. In addition, future imaging tools are poised to give us important insights into the underlying cardiovascular molecular pathology associated with cancer and oncological therapies. This review aims at giving an overview of the novel imaging technologies that have the potential to change cardio-oncological science and clinical practice in the near future.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 03 Apr 2022; 168:24-32
Yaros K, Eksi B, Chandra A, Agusala K, Lehmann LH, Zaha VG
J Mol Cell Cardiol: 03 Apr 2022; 168:24-32 | PMID: 35385715
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Abstract

Prostaglandin D signaling and cardiovascular homeostasis.

Kong D, Yu Y
Cardiovascular diseases are the leading cause of death worldwide. A chronic inflammatory response is a common pathological alteration in diverse cardiovascular diseases. Prostaglandin (PG) D2, a key lipid mediator derived from arachidonic acid metabolism, promotes resolution of inflammation and regulated T cell function through its receptors. Accumulated evidence has shown that dysregulated PGD2 signaling is involved in the pathogenesis of cardiovascular diseases, including atherosclerosis, hypertension, pulmonary hypertension, abdominal aortic aneurysm, and myocardial ischemia. Here, we summarized the recent progresses on PGD2 in cardiovascular homeostasis and discussed potential therapeutic translation by targeting PGD2 signaling.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 01 Apr 2022; 167:97-105
Kong D, Yu Y
J Mol Cell Cardiol: 01 Apr 2022; 167:97-105 | PMID: 35367459
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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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Abstract

Genetics of cancer therapy-associated cardiotoxicity.

Kim Y, Seidman JG, Seidman CE
As the number of cancer survivors has increased significantly over the last decades due to aging of population and development of effective cancer therapies, side effects from cancer therapies have been increasingly recognized. High-dose anthracyclines, immunotherapies, and concurrent radiation, as well as traditional cardiovascular risk factors such as smoking, hypertension, diabetes, hyperlipidemia, and obesity increase risks for unintended cardiovascular toxicity. However, these factors do not fully explain why only a subset of patients develop adverse cardiovascular sequelae from cancer therapies. Recent studies demonstrate that genetics play a substantial role in susceptibility to development of cardiovascular toxicities from cancer therapies. Common single nucleotide polymorphisms in multiple genes involved in various cellular pathways including membrane transport, stress response, and sarcomeres are recognized to increase risks for these toxicities. Pathogenic variants in the genes encoding proteins that comprise sarcomeres also contribute to cardiomyopathy following cancer therapies. Furthermore, genetic manipulations of model systems indicate mechanisms by which cardiotoxicities emerge following cancer immunomodulatory therapies. Continued efforts are needed to enable insights into cardiovascular responsiveness to these multi-targeted therapies, improve risk stratification of patients, and enable therapeutic interventions that limit these unintended adverse consequences from life-saving cancer treatments.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 28 Mar 2022; 167:85-91
Kim Y, Seidman JG, Seidman CE
J Mol Cell Cardiol: 28 Mar 2022; 167:85-91 | PMID: 35358500
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Abstract

Enhanced NCLX-dependent mitochondrial Ca efflux attenuates pathological remodeling in heart failure.

Garbincius JF, Luongo TS, Jadiya P, Hildebrand AN, ... Koch WJ, Elrod JW
Mitochondrial calcium (mCa2+) uptake couples changes in cardiomyocyte energetic demand to mitochondrial ATP production. However, excessive mCa2+ uptake triggers permeability transition and necrosis. Despite these established roles during acute stress, the involvement of mCa2+ signaling in cardiac adaptations to chronic stress remains poorly defined. Changes in NCLX expression are reported in heart failure (HF) patients and models of cardiac hypertrophy. Therefore, we hypothesized that altered mCa2+ homeostasis contributes to the hypertrophic remodeling of the myocardium that occurs upon a sustained increase in cardiac workload. The impact of mCa2+ flux on cardiac function and remodeling was examined by subjecting mice with cardiomyocyte-specific overexpression (OE) of the mitochondrial Na+/Ca2+ exchanger (NCLX), the primary mediator of mCa2+ efflux, to several well-established models of hypertrophic and non-ischemic HF. Cardiomyocyte NCLX-OE preserved contractile function, prevented hypertrophy and fibrosis, and attenuated maladaptive gene programs in mice subjected to chronic pressure overload. Hypertrophy was attenuated in NCLX-OE mice, prior to any decline in cardiac contractility. NCLX-OE similarly attenuated deleterious cardiac remodeling in mice subjected to chronic neurohormonal stimulation. However, cardiomyocyte NCLX-OE unexpectedly reduced overall survival in mice subjected to severe neurohormonal stress with angiotensin II + phenylephrine. Adenoviral NCLX expression limited mCa2+ accumulation, oxidative metabolism, and de novo protein synthesis during hypertrophic stimulation of cardiomyocytes in vitro. Our findings provide genetic evidence for the contribution of mCa2+ to early pathological remodeling in non-ischemic heart disease, but also highlight a deleterious consequence of increasing mCa2+ efflux when the heart is subjected to extreme, sustained neurohormonal stress.

Copyright © 2022 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 28 Mar 2022; 167:52-66
Garbincius JF, Luongo TS, Jadiya P, Hildebrand AN, ... Koch WJ, Elrod JW
J Mol Cell Cardiol: 28 Mar 2022; 167:52-66 | PMID: 35358843
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Abstract

Coronary vessel formation in development and regeneration: origins and mechanisms.

Tian X, Zhou B
Neovascularization of the ischemic myocardium following infarction is vital for the survival of cardiomyocytes and prevention of heart failure. However, the intrinsic revascularization following ischemic injury in the heart is inadequate to restore blood flow to the infarcted myocardium. A comprehensive understanding of how coronary vasculature is constructed and what developmental pathways might be reactivated after infarction is beneficial to develop effective strategies for heart revascularization. The latest lineage tracing studies of coronary vasculature have revealed multiple developmental origins for coronary vascular endothelial cells. The development and growth of coronary vessels emanated from different cellular origins are governed by distinct regulatory mechanisms. Here, we highlight recent research advancements on cellular sources and molecular mechanisms of coronary vessel formation during heart development and regeneration, and also elaborate on how these mechanisms can be reactivated or recapitulated to facilitate therapeutic revascularization in ischemic heart disease.

Copyright © 2022. Published by Elsevier Ltd.

J Mol Cell Cardiol: 27 Mar 2022; 167:67-82
Tian X, Zhou B
J Mol Cell Cardiol: 27 Mar 2022; 167:67-82 | PMID: 35354073
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This program is still in alpha version.