Journal: J Mol Cell Cardiol

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Abstract
<div><h4>Metabolism-based cardiomyocytes production for regenerative therapy.</h4><i>Umei TC, Tohyama S, Fukuda K</i><br /><AbstractText>Human pluripotent stem cells (hPSCs) are currently used in clinical applications such as cardiac regenerative therapy, studying disease models, and drug screening for heart failure. Transplantation of hPSC-derived cardiomyocytes (hPSC-CMs) can be used as an alternative therapy for heart transplantation. In contrast to differentiated somatic cells, hPSCs possess unique metabolic programs to maintain pluripotency, and understanding their metabolic features can contribute to the development of technologies that can be useful for their clinical applications. The production of hPSC-CMs requires stepwise specification during embryonic development and metabolic regulation is crucial for proper embryonic development. These metabolic features have been applied to hPSC-CM production methods, such as mesoderm induction, specifications for cardiac progenitors, and their maturation. This review describes the metabolic programs in hPSCs and the metabolic regulation in hPSC-CM production for cardiac regenerative therapy.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 18 Jan 2023; epub ahead of print</small></div>
Umei TC, Tohyama S, Fukuda K
J Mol Cell Cardiol: 18 Jan 2023; epub ahead of print | PMID: 36681267
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<div><h4>Resting membrane potential is less negative in trabeculae from right atrial appendages of women, but action potential duration does not shorten with age.</h4><i>Pecha S, Ismaili D, Geelhoed B, Knaut M, ... Christ T, Ravens U</i><br /><b>Aims</b><br />The incidence of atrial fibrillation (AF) increases with age. Women have a lower risk. Little is known on the impact of age, sex and clinical variables on action potentials (AP) recorded in right atrial tissue obtained during open heart surgery from patients in sinus rhythm (SR) and in longstanding AF. We here investigated whether age or sex have an impact on the shape of AP recorded in vitro from right atrial tissue.<br /><b>Methods</b><br />We performed multivariable analysis of individual AP data from trabeculae obtained during heart surgery of patients in SR (n = 320) or in longstanding AF (n = 201). AP were recorded by sharp microelectrodes at 37 °C at 1 Hz. Impact of clinical variables were modeled using a multivariable mixed model regression.<br /><b>Results</b><br />In SR, AP duration at 90% repolarization (APD<sub>90</sub>) increased with age. Lower ejection fraction and higher body mass index were associated with smaller action potential amplitude (APA) and maximum upstroke velocity (V<sub>max</sub>). The use of beta-blockers was associated with larger APD<sub>90</sub>. In tissues from women, resting membrane potential was less negative and APA as well as V<sub>max</sub> were smaller. Besides shorter APD<sub>20</sub> in elderly patients, effects of age and sex on atrial AP were lost in AF.<br /><b>Conclusion</b><br />The higher probability to develop AF at advanced age cannot be explained by a shortening in APD<sub>90</sub>. Less negative RMP and lower upstroke velocity might contribute to lower incidence of AF in women, which may be of clinical relevance.<br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 18 Jan 2023; epub ahead of print</small></div>
Pecha S, Ismaili D, Geelhoed B, Knaut M, ... Christ T, Ravens U
J Mol Cell Cardiol: 18 Jan 2023; epub ahead of print | PMID: 36681268
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<div><h4>VGLL4-TEAD1 promotes vascular smooth muscle cell differentiation from human pluripotent stem cells via TET2.</h4><i>Wang Z, Quan Y, Hu M, Xu Y, ... Li M, Wang Y</i><br /><AbstractText>The Hippo signaling pathway plays a critical role in cardiovascular development and stem cell differentiation. Using microarray profiling, we found that the Hippo pathway components vestigial-like family member 4 (VGLL4) and TEA domain transcription factor 1 (TEAD1) were upregulated during vascular smooth muscle cell (VSMC) differentiation from H1 ESCs (.H1 embryonic stem cells) To further explore the role and molecular mechanisms of VGLL4 in regulating VSMC differentiation, we generated a VGLL4-knockdown H1 ESC line (heterozygous knockout) using the CRISPR/Cas9 system and found that VGLL4 knockdown inhibited VSMC specification. In contrast, overexpression of VGLL4 using the PiggyBac transposon system facilitated VSMC differentiation. We confirmed that this effect was mediated via TEAD1 and VGLL4 interaction. In addition, bioinformatics analysis revealed that Ten-eleven-translocation 2 (TET2), a DNA demethylase, is a target of TEAD1, and a luciferase assay further verified that TET2 is the target of the VGLL4-TEAD1 complex. Indeed, TET2 overexpression promoted VSMC marker gene expression and countered the VGLL4 knockdown-mediated inhibitory effects on VSMC differentiation. In summary, we revealed a novel role of VGLL4 in promoting VSMC differentiation from hESCs and identified TET2 as a new target of the VGLL4-TEAD1 complex, which may demethylate VSMC marker genes and facilitate VSMC differentiation. This study provides new insights into the VGLL4-TEAD1-TET2 axis in VSMC differentiation and vascular development.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 16 Jan 2023; epub ahead of print</small></div>
Wang Z, Quan Y, Hu M, Xu Y, ... Li M, Wang Y
J Mol Cell Cardiol: 16 Jan 2023; epub ahead of print | PMID: 36657637
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<div><h4>Integrated proteomics reveals alterations in sarcomere composition and developmental processes during postnatal swine heart development.</h4><i>Aballo TJ, Roberts DS, Bayne EF, Zhu W, ... Zhang J, Ge Y</i><br /><AbstractText>The neonatal swine heart possesses an endogenous ability to regenerate injured myocardium through the proliferation of pre-existing cardiomyocyte (CM) populations. However, this regenerative capacity is lost shortly after birth. Normal postnatal developmental processes and the regenerative capacity of mammalian hearts are tightly linked, but not much is known about how the swine cardiac proteome changes throughout postnatal development. Herein, we integrated robust and quantitative targeted \"top-down\" and global \"bottom-up\" proteomic workflows to comprehensively define the dynamic landscape of the swine cardiac proteome throughout postnatal maturation. Using targeted top-down proteomics, we were able to identify significant alterations in sarcomere composition, providing new insight into the proteoform landscape of sarcomeres that can disassemble, a process necessary for productive CM proliferation. Furthermore, we quantified global changes in protein abundance using bottom-up proteomics, identified over 700 differentially expressed proteins throughout postnatal development, and mapped these proteins to changes in developmental and metabolic processes. We envision these results will help guide future investigations to comprehensively understand endogenous cardiac regeneration toward the development of novel therapeutic strategies for heart failure.</AbstractText><br /><br />Copyright © 2023. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 16 Jan 2023; epub ahead of print</small></div>
Aballo TJ, Roberts DS, Bayne EF, Zhu W, ... Zhang J, Ge Y
J Mol Cell Cardiol: 16 Jan 2023; epub ahead of print | PMID: 36657638
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<div><h4>Myh6 promoter-driven Cre recombinase excises floxed DNA fragments in a subset of male germline cells.</h4><i>Sheldon C, Kessinger CW, Sun Y, Kontaridis MI, ... Zhang H, Lin Z</i><br /><AbstractText>Myh6-Cre transgenic mouse line was known to express Cre recombinase only in the heart. Nevertheless, during breeding Myh6-Cre to Rosa26<sup>fstdTom</sup> reporter (tdTom) mouse line, we observed that a significant part of their F2 tdTom/+ offspring had tdTom reporter gene universally activated. Our results show that Myh6-Cre transgenic mice have Cre recombinase activity in a subpopulation of the male germline cells, and that Myh6 gene transcripts are enriched in the interstitial Leydig cells and the undifferentiated spermatogonia stem cells. In summary, the current study confirms that the previously known \"heart-specific\" Myh6 promoter drives Cre expression in the testis.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 28 Dec 2022; 175:62-66</small></div>
Sheldon C, Kessinger CW, Sun Y, Kontaridis MI, ... Zhang H, Lin Z
J Mol Cell Cardiol: 28 Dec 2022; 175:62-66 | PMID: 36584478
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<div><h4>DELE1 is protective for mitochondrial cardiomyopathy.</h4><i>Huynh H, Zhu S, Lee S, Bao Y, ... Evans SM, Fang X</i><br /><AbstractText>Mitochondrial dysfunction in heart triggers an integrated stress response (ISR) through phosphorylation of eIF2α and subsequent ATF4 activation. DAP3 Binding Cell Death Enhancer 1 (DELE1) is a mitochondrial protein recently found to be critical for mediating mitochondrial stress-triggered ISR (MSR)-induced eIF2α-ATF4 pathway activation. However, the specific role of DELE1 in heart at baseline or in response to mitochondrial stress remains largely unknown. In this study, we report that DELE1 is dispensable for cardiac development and function under baseline conditions. Conversely, DELE1 is essential for mediating an adaptive response to mitochondrial dysfunction-triggered stress in the heart, playing a protective role in mitochondrial cardiomyopathy.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 17 Dec 2022; epub ahead of print</small></div>
Huynh H, Zhu S, Lee S, Bao Y, ... Evans SM, Fang X
J Mol Cell Cardiol: 17 Dec 2022; epub ahead of print | PMID: 36539111
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<div><h4>CaMKII and reactive oxygen species contribute to early reperfusion arrhythmias, but oxidation of CaMKIIδ at methionines 281/282 is not a determining factor.</h4><i>Hansen MH, Sadredini M, Hasic A, Anderson ME, Sjaastad I, Stokke MK</i><br /><b>Background</b><br />Available evidence suggest that Ca<sup>2+</sup>/calmodulin-dependent protein kinase type IIδ (CaMKIIδ) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKIIδ by oxidation of two methionines at positions 281/282, oxidized-CaMKIIδ (Ox-CaMKIIδ) has been proposed to be important for IRA. However, direct evidence for this is missing.<br /><b>Methods</b><br />We exposed Langendorff-perfused hearts and ventricular cardiomyocytes from C57BL/6 mice to global and simulated ischemia, respectively, and recorded arrhythmic events during early reperfusion. Hearts were collected for immunoblotting of key phosphoproteins. We evaluated the effects of beta-adrenoceptor stimulation, inhibition of CaMKII, and reduced ROS levels with isoprenaline, KN93/AIP and N-acetylcysteine (NAC), respectively. We further tested the importance of Ox-CaMKIIδ by using hearts and cardiomyocytes from mice with CaMKIIδ resistant to oxidation of methionines 281 and 282 (MMVV).<br /><b>Results</b><br />Hearts treated with KN93, AIP or NAC had lower incidence of early IRA, and NAC-treated cardiomyocytes had lower incidence of arrhythmogenic events. However, hearts from MMVV mice had a similar incidence of early IRA to wild type mice (WT), and MMVV and WT cardiomyocytes had a similar frequency of Ca<sup>2+</sup> waves and Ca<sup>2+</sup> sparks. Immunoblotting confirmed high levels of oxidation in early reperfusion, but revealed no significant differences in the phosphorylation levels of Ca<sup>2+</sup>-handling proteins in MMVV and WT hearts.<br /><b>Conclusions</b><br />Although CaMKII and ROS both contribute to early IRA, hearts from mice with CaMKII resistant to oxidation at methionines 281/282 were not protected from such arrhythmias, suggesting that oxidation at these sites is not a determining factor.<br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 14 Dec 2022; epub ahead of print</small></div>
Hansen MH, Sadredini M, Hasic A, Anderson ME, Sjaastad I, Stokke MK
J Mol Cell Cardiol: 14 Dec 2022; epub ahead of print | PMID: 36528076
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<div><h4>Klf4 deficiency exacerbates myocardial ischemia/reperfusion injury in mice via enhancing ROCK1/DRP1 pathway-dependent mitochondrial fission.</h4><i>Li Y, Xiong Z, Jiang Y, Zhou H, ... Tian F, Chen Y</i><br /><b>Rational</b><br />Excessive mitochondrial fission is considered key process involved in myocardial ischemia/reperfusion (I/R) injury. However, the upstream mechanism remains largely unclear. Decreased level of Kruppel Like Factor 4 (KLF4) has been implicated in the pathogenesis of mitochondrial dysfunction and heart\'s adaption to stress. However, the role of Klf4 in I/R process is not fully elucidated. This study aims to investigate how Klf4 regulates mitochondrial dynamics and further clarify its underlying mechanism during cardiac I/R injury.<br /><b>Methods</b><br />Loss-of-function and gain-of-function strategies were applied to investigate the role of Klf4 in cardiac I/R injury via genetic ablation or intra-myocardial adenovirus injection. Mitochondrial dynamics was analyzed by confocal microscopy in vitro and transmission electron microscopy in vivo. Chromatin immunoprecipitation and luciferase reporter assay were performed to explore the underlying mechanisms.<br /><b>Results</b><br />KLF4 was downregulated in I/R heart. Cardiac-specific Klf4 knockout significantly exacerbated cardiac dysfunction in I/R mice. Mechanistically, Klf4 deficiency aggravated mitochondrial apoptosis, reduced ATP generation and boosted ROS overproduction via enhancing DRP1-dependent mitochondrial fission. ROCK1 was identified as a kinase regulating DRP1 activity at Ser616. Klf4 deficiency upregulated the expression of ROCK1 at transcriptional level, thus increasing S616-DRP1-mediated mitochondrial fission during I/R. Finally, reconstitution of Klf4 inhibited mitochondrial fission, restored mitochondrial function and alleviated I/R injury.<br /><b>Conclusion</b><br />Our study provides the first evidence that Klf4 deficiency exacerbates myocardial I/R injury through regulating ROCK1 expression at transcriptional level to induce DRP1-mediated mitochondrial fission. Targeting mitochondrial dynamics by restoring Klf4 might be potentially cardio-protective strategies attenuating I/R injury.<br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 09 Dec 2022; 174:115-132</small></div>
Li Y, Xiong Z, Jiang Y, Zhou H, ... Tian F, Chen Y
J Mol Cell Cardiol: 09 Dec 2022; 174:115-132 | PMID: 36509022
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<div><h4>Multi-omics analyses identify molecular signatures with prognostic values in different heart failure aetiologies.</h4><i>Aboumsallem JP, Shi C, De Wit S, Markousis-Mavrogenis G, ... Silljé HHW, De Boer RA</i><br /><b>Background</b><br />Heart failure (HF) is the leading cause of morbidity and mortality worldwide, and there is an urgent need for more global studies and data mining approaches to uncover its underlying mechanisms. Multiple omics techniques provide a more holistic molecular perspective to study pathophysiological events involved in the development of HF.<br /><b>Methods</b><br />In this study, we used a label-free whole myocardium multi-omics characterization from three commonly used mouse HF models: transverse aortic constriction (TAC), myocardial infarction (MI), and homozygous Phospholamban-R14del (PLN-R14<sup>Δ/Δ</sup>). Genes, proteins, and metabolites were analysed for differential expression between each group and a corresponding control group. The core transcriptome and proteome datasets were used for enrichment analysis. For genes that were upregulated at both the RNA and protein levels in all models, clinical validation was performed by means of plasma level determination in patients with HF from the BIOSTAT-CHF cohort.<br /><b>Results</b><br />Cell death and tissue repair-related pathways were upregulated in all preclinical models. Fatty acid oxidation, ATP metabolism, and Energy derivation processes were downregulated in all investigated HF aetiologies. Putrescine, a metabolite known for its role in cell survival and apoptosis, demonstrated a 4.9-fold (p < 0.02) increase in PLN-R14<sup>Δ/Δ</sup>, 2.7-fold (p < 0.005) increase in TAC mice, and 2.2-fold (p < 0.02) increase in MI mice. Four Biomarkers were associated with all-cause mortality (PRELP: Hazard ratio (95% confidence interval) 1.79(1.35, 2.39), p < 0.001; CKAP4: 1.38(1.21, 1.57), p < 0.001; S100A11: 1.37(1.13, 1.65), p = 0.001; Annexin A1 (ANXA1): 1.16(1.04, 1.29) p = 0.01), and three biomarkers were associated with HF-Related Rehospitalization, (PRELP: 1.88(1.4, 2.53), p < 0.001; CSTB: 1.15(1.05, 1.27), p = 0.003; CKAP4: 1.18(1.02, 1.35), P = 0.023).<br /><b>Conclusions</b><br />Cell death and tissue repair pathways were significantly upregulated, and ATP and energy derivation processes were significantly downregulated in all models. Common pathways and biomarkers with potential clinical and prognostic associations merit further investigation to develop optimal management and therapeutic strategies for all HF aetiologies.<br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 06 Dec 2022; epub ahead of print</small></div>
Aboumsallem JP, Shi C, De Wit S, Markousis-Mavrogenis G, ... Silljé HHW, De Boer RA
J Mol Cell Cardiol: 06 Dec 2022; epub ahead of print | PMID: 36493852
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<div><h4>Cardiac injection of USSC boosts remuscularization of the infarcted heart by shaping the T-cell response.</h4><i>Ding Z, Tan K, Alter C, Temme S, ... Kögler G, Schrader J</i><br /><AbstractText>Regenerating the injured heart remains one of the most vexing challenges in cardiovascular medicine. Cell therapy has shown potential for treatment of myocardial infarction, but low cell retention so far has limited its success. Here we show that intramyocardial injection of highly apoptosis-resistant unrestricted somatic stem cells (USSC) into infarcted rat hearts resulted in an unprecedented thickening of the left ventricular wall with cTnT<sup>+</sup>/BrdU<sup>+</sup> cardiomyocytes that was paralleled by progressively restored ejection fraction. USSC induced significant T-cell enrichment in ischemic tissue with enhanced expression of T-cell related cytokines. Inhibition of T-cell activation by anti-CD28 monoclonal antibody, fully abolished the regenerative response which was restored by adoptive T-cell transfer. Secretome analysis of USSC and lineage tracing studies suggest that USSC secrete paracrine factors over an extended period of time which boosts a T-cell driven endogenous regenerative response mainly from adult cardiomyocytes.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 06 Dec 2022; epub ahead of print</small></div>
Ding Z, Tan K, Alter C, Temme S, ... Kögler G, Schrader J
J Mol Cell Cardiol: 06 Dec 2022; epub ahead of print | PMID: 36493853
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<div><h4>Distinct effects of intracellular vs. extracellular acidic pH on the cardiac metabolome during ischemia and reperfusion.</h4><i>Milliken AS, Ciesla JH, Nadtochiy SM, Brookes PS</i><br /><AbstractText>Tissue ischemia results in intracellular pH (pH<sub>IN</sub>) acidification, and while metabolism is a known driver of acidic pH<sub>IN</sub>, less is known about how acidic pH<sub>IN</sub> regulates metabolism. Furthermore, acidic extracellular (pH<sub>EX</sub>) during early reperfusion confers cardioprotection, but how this impacts metabolism is unclear. Herein we employed LCMS based targeted metabolomics to analyze perfused mouse hearts exposed to: (i) control perfusion, (ii) hypoxia, (iii) ischemia, (iv) enforced acidic pH<sub>IN</sub>, (v) control reperfusion, and (vi) acidic pH<sub>EX</sub> (6.8) reperfusion. Surprisingly little overlap was seen between metabolic changes induced by hypoxia, ischemia, and acidic pH<sub>IN</sub>. Acidic pH<sub>IN</sub> elevated metabolites in the top half of glycolysis, and enhanced glutathione redox state. Meanwhile, acidic pH<sub>EX</sub> reperfusion induced substantial metabolic changes in addition to those seen in control reperfusion. This included elevated metabolites in the top half of glycolysis, prevention of purine nucleotide loss, and an enhancement in glutathione redox state. These data led to hypotheses regarding potential roles for methylglyoxal inhibiting the mitochondrial permeability transition pore, and for acidic inhibition of ecto-5\'-nucleotidase, as potential mediators of cardioprotection by acidic pH<sub>EX</sub> reperfusion. However, neither hypothesis was supported by subsequent experiments. In contrast, analysis of cardiac effluents revealed complex effects of pH<sub>EX</sub> on metabolite transport, suggesting that mildly acidic pH<sub>EX</sub> may enhance succinate release during reperfusion. Overall, each intervention had distinct and overlapping metabolic effects, suggesting acidic pH is an independent metabolic regulator regardless which side of the cell membrane it is imposed.</AbstractText><br /><br />Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.<br /><br /><small>J Mol Cell Cardiol: 05 Dec 2022; 174:101-114</small></div>
Milliken AS, Ciesla JH, Nadtochiy SM, Brookes PS
J Mol Cell Cardiol: 05 Dec 2022; 174:101-114 | PMID: 36481511
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<div><h4>Adenosine kinase promotes post-infarction cardiac repair by epigenetically maintaining reparative macrophage phenotype.</h4><i>Zhang M, Wang C, Wang R, Xu J, ... Huo Y, Dong S</i><br /><AbstractText>Pro-inflammatory and reparative macrophages are crucial in clearing necrotic myocardium and promoting cardiac repair after myocardial infarction (MI), respectively. Extracellular adenosine has been demonstrated to modulate macrophage polarization through adenosine receptors. However, the role of intracellular adenosine in macrophage polarization has not been explored and adenosine kinase (ADK) is a major enzyme regulating intracellular adenosine levels. Here, we aimed to elucidate the role of ADK in macrophage polarization and its subsequent impact on MI. We demonstrated that ADK was upregulated in bone marrow-derived macrophages (BMDMs) after IL-4 treatment and was highly expressed in the infarct area at day 7 post-MI, especially in macrophages. Compared with wild-type mice, myeloid-specific Adk knockout mice showed increased infarct size, limited myofibroblast differentiation, reduced collagen deposition and more severe cardiac dysfunction after MI, which was related to impaired reparative macrophage phenotype in MI tissue. We found that ADK deletion or inhibition significantly decreased the expression of reparative genes, such as Arg1, Ym1, Fizz1, and Cd206 in BMDMs after IL-4 treatment. The increased intracellular adenosine due to Adk deletion inhibited transmethylation reactions and decreased the trimethylation of H3K4 in BMDMs after IL-4 treatment. Mechanistically, we demonstrated that Adk deletion suppressed reparative macrophage phenotype through decreased IRF4 expression, which resulted from reduced levels of H3K4me3 on the Irf4 promotor. Together, our study reveals that ADK exerts a protective effect against MI by promoting reparative macrophage polarization through epigenetic mechanisms.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 03 Dec 2022; 174:88-100</small></div>
Zhang M, Wang C, Wang R, Xu J, ... Huo Y, Dong S
J Mol Cell Cardiol: 03 Dec 2022; 174:88-100 | PMID: 36473288
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<div><h4>dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.</h4><i>Mhatre KN, Murray JD, Flint G, McMillen TS, ... Moussavi-Harami F, Regnier M</i><br /><AbstractText>Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ~1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 02 Dec 2022; epub ahead of print</small></div>
Mhatre KN, Murray JD, Flint G, McMillen TS, ... Moussavi-Harami F, Regnier M
J Mol Cell Cardiol: 02 Dec 2022; epub ahead of print | PMID: 36470336
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<div><h4>Reactive oxygen species-induced long intergenic noncoding RNA p21 accelerates abdominal aortic aneurysm formation by promoting secretary smooth muscle cell phenotypes.</h4><i>Wang S, Wang J, Cai D, Li X, ... Xiu J, Bin J</i><br /><AbstractText>Whether long noncoding RNAs participate in the formation of abdominal aortic aneurysms (AAAs) through the regulation of SMC phenotypic switching is unknown. lincRNA-p21 induced by reactive oxygen species (ROS) is likely functionally associated with SMC phenotypic switching. We thus investigated the role of lincRNA-p21 in SMC phenotypic switching-associated AAA formation and its underlying mechanisms. An analysis of human and mouse abdominal aortic samples revealed that the lincRNA-p21 levels were significantly higher in AAA tissue. Stimulation with hydrogen peroxide upregulated the expression of lincRNA-p21 in a dose-dependent manner and converted SMCs from a contractile phenotype to a synthetic, proteolytic, and proinflammatory phenotype in vitro. Moreover, lincRNA-p21 promoted fracture of elastic fibres, reconstruction of the vascular wall, and AAA formation in vivo by modulating SMC phenotypic switching in two mouse models of AAA induced by angiotensin II or porcine pancreatic elastase (PPE) perfusion. Using a bioinformatics prediction method and luciferase reporter gene assays, we further proved that lincRNA-p21 sponged miR-204-5p to release the transcriptional activity of Mekk3 and promoted the NF-κB pathway and thereby played a role in the SMC phenotypic switch and AAA formation. The ROS levels were positively correlated with the lincRNA-p21 levels in human and mouse AAA tissues. The knockdown of lincRNA-p21 in a PPE-induced mouse AAA model increased the miR-204-5p levels and reduced the expression of Mekk3, whereas lincRNA-p21 overexpression had the opposite effect. Collectively, the results indicated that ROS-induced lincRNA-p21 sponges miR-204-5p to accelerate synthetic and proinflammatory SMC phenotypes through the Mekk3/NF-κB pathway in AAA formation. Thus, lincRNA-p21 may have therapeutic potential for AAA formation.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 24 Nov 2022; 174:63-76</small></div>
Wang S, Wang J, Cai D, Li X, ... Xiu J, Bin J
J Mol Cell Cardiol: 24 Nov 2022; 174:63-76 | PMID: 36436251
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<div><h4>Mitochondrial permeability transition pore-dependent necrosis.</h4><i>Robichaux DJ, Harata M, Murphy E, Karch J</i><br /><AbstractText>Mitochondrial permeability transition pore (mPTP)-dependent cell death is a form of necrotic cell death that is driven by mitochondrial dysfunction by the opening of the mPTP and is triggered by increases in matrix levels of Ca<sup>2+</sup> and reactive oxygen species. This form of cell death has been implicated in ischemic injuries of the heart and brain as well as numerous degenerative diseases in the brain and skeletal muscle. This review focuses on the molecular triggers and regulators of mPTP-dependent necrosis in the context of myocardial ischemia reperfusion injury. Research over the past 50 years has led to the identity of regulators and putative pore-forming components of the mPTP. Finally, downstream consequences of activation of the mPTP as well as ongoing questions and areas of research are discussed. These questions pose a particular interest as targeting the mPTP could potentially represent an efficacious therapeutic strategy to reduce infarct size following an ischemic event.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>J Mol Cell Cardiol: 21 Nov 2022; 174:47-55</small></div>
Robichaux DJ, Harata M, Murphy E, Karch J
J Mol Cell Cardiol: 21 Nov 2022; 174:47-55 | PMID: 36410526
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<div><h4>Endothelial SIRT6 deficiency promotes arterial thrombosis in mice.</h4><i>Gaul DS, Calatayud N, Pahla J, Bonetti NR, ... Camici GG, Matter CM</i><br /><b>Objective</b><br />Arterial thrombosis may be initiated by endothelial inflammation or denudation, activation of blood-borne elements or the coagulation system. Tissue factor (TF), a central trigger of the coagulation cascade, is regulated by the pro-inflammatory NF-κB-dependent pathways. Sirtuin 6 (SIRT6) is a nuclear member of the sirtuin family of NAD<sup>+</sup>-dependent deacetylases and is known to inhibit NF-κB signaling. Its constitutive deletion in mice shows early lethality with hypoglycemia and accelerated aging. Of note, the role of SIRT6 in arterial thrombosis remains unknown. Thus, we hypothesized that endothelial SIRT6 protects from arterial thrombosis by modulating inhibition of NF-κB-associated pathways.<br /><b>Approach and results</b><br />Using a laser-induced carotid thrombosis model, in vivo arterial occlusion occurred 45% faster in 12-week-old male endothelial-specific Sirt6<sup>-/-</sup> mice as compared to Sirt6<sup>fl/fl</sup> controls (n ≥ 9 per group; p = 0.0012). Levels of procoagulant TF were increased in animals lacking endothelial SIRT6 as compared to control littermates. Similarly, in cultured human aortic endothelial cells, SIRT6 knockdown increased TF mRNA, protein and activity. Moreover, SIRT6 knockdown increased mRNA levels of NF-κB-associated genes tumor necrosis factor alpha (TNF-α), poly [ADP-ribose] polymerase 1 (PARP-1), vascular cell adhesion molecule 1 (VCAM-1), and cyclooxygenase-2 (COX-2); at the protein level, COX-2, VCAM-1, TNF-α, and cleaved PARP-1 remained increased after Sirt6 knockdown.<br /><b>Conclusions</b><br />Endothelium-specific Sirt6 deletion promotes arterial thrombosis in mice. In cultured human aortic endothelial cells, SIRT6 silencing enhances TF expression and activates pro-inflammatory pathways including TNF-α, cleaved PARP-1, VCAM-1 and COX-2. Hence, endogenous endothelial SIRT6 exerts a protective role in experimental arterial thrombosis.<br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 19 Nov 2022; epub ahead of print</small></div>
Gaul DS, Calatayud N, Pahla J, Bonetti NR, ... Camici GG, Matter CM
J Mol Cell Cardiol: 19 Nov 2022; epub ahead of print | PMID: 36414111
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<div><h4>Intracoronary transplantation of pluripotent stem cell-derived cardiomyocytes: Inefficient procedure for cardiac regeneration.</h4><i>Kobayashi H, Tohyama S, Kanazawa H, Ichimura H, ... Shiba Y, Fukuda K</i><br /><AbstractText>Advances in stem cell biology have facilitated cardiac regeneration, and many animal studies and several initial clinical trials have been conducted using human pluripotent stem cell-derived cardiomyocytes (PSC-CMs). Most preclinical and clinical studies have typically transplanted PSC-CMs via the following two distinct approaches: direct intramyocardial injection or epicardial delivery of engineered heart tissue. Both approaches present common disadvantages, including a mandatory thoracotomy and poor engraftment. Furthermore, a standard transplantation approach has yet to be established. In this study, we tested the feasibility of performing intracoronary administration of PSC-CMs based on a commonly used method of transplanting somatic stem cells. Six male cynomolgus monkeys underwent intracoronary administration of dispersed human PSC-CMs or PSC-CM aggregates, which are called cardiac spheroids, with multiple cell dosages. The recipient animals were sacrificed at 4 weeks post-transplantation for histological analysis. Intracoronary administration of dispersed human PSC-CMs in the cynomolgus monkeys did not lead to coronary embolism or graft survival. Although the transplanted cardiac spheroids became partially engrafted, they also induced scar formation due to cardiac ischemic injury. Cardiac engraftment and scar formation were reasonably consistent with the spheroid size or cell dosage. These findings indicate that intracoronary transplantation of PSC-CMs is an inefficient therapeutic approach.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 17 Nov 2022; epub ahead of print</small></div>
Kobayashi H, Tohyama S, Kanazawa H, Ichimura H, ... Shiba Y, Fukuda K
J Mol Cell Cardiol: 17 Nov 2022; epub ahead of print | PMID: 36403760
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Abstract
<div><h4>Iron homeostasis in the heart: Molecular mechanisms and pharmacological implications.</h4><i>Zhang J, Song Y, Li Y, Lin HB, Fang X</i><br /><AbstractText>Iron is necessary for the life of practically all living things, yet it may also harm people toxically. Accordingly, humans and other mammals have evolved an effective and tightly regulatory system to maintain iron homeostasis in healthy tissues, including the heart. Iron deficiency is common in patients with heart failure, and is associated with worse prognosis in this population; while the prevalence of iron overload-related cardiovascular disorders is also increasing. Therefore, enhancing the therapy of patients with cardiovascular disorders requires a thorough understanding of iron homeostasis. Here, we give readers an overview of the fundamental mechanisms governing systemic iron homeostasis as well as the most recent knowledge about the intake, storage, use, and export of iron from the heart. Genetic mouse models used for investigation of iron metabolism in various in vivo scenarios are summarized and highlighted. We also go through different clinical conditions and therapeutic approaches that target cardiac iron dyshomeostasis. Finally, we conclude the review by outlining the present knowledge gaps and important open questions in this field in order to guide future research on cardiac iron metabolism.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>J Mol Cell Cardiol: 11 Nov 2022; 174:15-24</small></div>
Zhang J, Song Y, Li Y, Lin HB, Fang X
J Mol Cell Cardiol: 11 Nov 2022; 174:15-24 | PMID: 36375319
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Abstract
<div><h4>Signaling network model of cardiomyocyte morphological changes in familial cardiomyopathy.</h4><i>Khalilimeybodi A, Riaz M, Campbell SG, Omens JH, ... Qyang Y, Saucerman JJ</i><br /><AbstractText>Familial cardiomyopathy is a precursor of heart failure and sudden cardiac death. Over the past several decades, researchers have discovered numerous gene mutations primarily in sarcomeric and cytoskeletal proteins causing two different disease phenotypes: hypertrophic (HCM) and dilated (DCM) cardiomyopathies. However, molecular mechanisms linking genotype to phenotype remain unclear. Here, we employ a systems approach by integrating experimental findings from preclinical studies (e.g., murine data) into a cohesive signaling network to scrutinize genotype to phenotype mechanisms. We developed an HCM/DCM signaling network model utilizing a logic-based differential equations approach and evaluated model performance in predicting experimental data from four contexts (HCM, DCM, pressure overload, and volume overload). The model has an overall prediction accuracy of 83.8%, with higher accuracy in the HCM context (90%) than DCM (75%). Global sensitivity analysis identifies key signaling reactions, with calcium-mediated myofilament force development and calcium-calmodulin kinase signaling ranking the highest. A structural revision analysis indicates potential missing interactions that primarily control calcium regulatory proteins, increasing model prediction accuracy. Combination pharmacotherapy analysis suggests that downregulation of signaling components such as calcium, titin and its associated proteins, growth factor receptors, ERK1/2, and PI3K-AKT could inhibit myocyte growth in HCM. In experiments with patient-specific iPSC-derived cardiomyocytes (MLP-W4R;MYH7-R723C iPSC-CMs), combined inhibition of ERK1/2 and PI3K-AKT rescued the HCM phenotype, as predicted by the model. In DCM, PI3K-AKT-NFAT downregulation combined with upregulation of Ras/ERK1/2 or titin or Gq protein could ameliorate cardiomyocyte morphology. The model results suggest that HCM mutations that increase active force through elevated calcium sensitivity could increase ERK activity and decrease eccentricity through parallel growth factors, Gq-mediated, and titin pathways. Moreover, the model simulated the influence of existing medications on cardiac growth in HCM and DCM contexts. This HCM/DCM signaling model demonstrates utility in investigating genotype to phenotype mechanisms in familial cardiomyopathy.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>J Mol Cell Cardiol: 10 Nov 2022; 174:1-14</small></div>
Khalilimeybodi A, Riaz M, Campbell SG, Omens JH, ... Qyang Y, Saucerman JJ
J Mol Cell Cardiol: 10 Nov 2022; 174:1-14 | PMID: 36370475
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Abstract
<div><h4>HuR-dependent expression of Wisp1 is necessary for TGFβ-induced cardiac myofibroblast activity.</h4><i>Green LC, Slone S, Anthony SR, Guarnieri AR, ... Kanisicak O, Tranter M</i><br /><AbstractText>Cardiac fibrosis is regulated by the activation and phenotypic switching of quiescent cardiac fibroblasts to active myofibroblasts, which have extracellular matrix (ECM) remodeling and contractile functions which play a central role in cardiac remodeling in response to injury. Here, we show that expression and activity of the RNA binding protein HuR is increased in cardiac fibroblasts upon transformation to an active myofibroblast. Pharmacological inhibition of HuR significantly blunts the TGFβ-dependent increase in ECM remodeling genes, total collagen secretion, in vitro scratch closure, and collagen gel contraction in isolated primary cardiac fibroblasts, suggesting a suppression of TGFβ-induced myofibroblast activation upon HuR inhibition. We identified twenty-four mRNA transcripts that were enriched for HuR binding following TGFβ treatment via photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). Eleven of these HuR-bound mRNAs also showed significant co-expression correlation with HuR, αSMA, and periostin in primary fibroblasts isolated from the ischemic-zone of infarcted mouse hearts. Of these, Wnt1-inducible signaling pathway protein-1 (Wisp1; Ccn4), was the most significantly associated with HuR expression in fibroblasts. Accordingly, we found Wisp1 expression to be increased in cardiac fibroblasts isolated from the ischemic-zone of mouse hearts following ischemia/reperfusion, and confirmed Wisp1 expression to be HuR-dependent in isolated fibroblasts. Finally, addition of exogenous recombinant Wisp1 partially rescued myofibroblast-induced collagen gel contraction following HuR inhibition, demonstrating that HuR-dependent Wisp1 expression plays a functional role in HuR-dependent MF activity downstream of TGFβ. In conclusion, HuR activity is necessary for the functional activation of primary cardiac fibroblasts in response to TGFβ, in part through post-transcriptional regulation of Wisp1.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 10 Nov 2022; epub ahead of print</small></div>
Green LC, Slone S, Anthony SR, Guarnieri AR, ... Kanisicak O, Tranter M
J Mol Cell Cardiol: 10 Nov 2022; epub ahead of print | PMID: 36372279
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Abstract
<div><h4>An endogenous inhibitor of angiogenesis downregulated by hypoxia in human aortic valve stenosis promotes disease pathogenesis.</h4><i>Lewis CTA, Mascall KS, Wilson HM, Murray F, ... Small GR, Nixon GF</i><br /><AbstractText>Aortic valve stenosis is the most common valve disease in the western world. Central to the pathogenesis of this disease is the growth of new blood vessels (angiogenesis) within the aortic valve allowing infiltration of immune cells and development of intra-valve inflammation. Identifying the cellular mediators involved in this angiogenesis is important as this may reveal new therapeutic targets which could ultimately prevent the progression of aortic valve stenosis. Aortic valves from patients undergoing surgery for aortic valve replacement or dilation of the aortic arch were examined both ex vivo and in vitro. We now demonstrate that the anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), a non-signalling soluble receptor for vascular endothelial growth factor, is constitutively expressed in non-diseased valves. sFlt-1 expression was, however, significantly reduced in aortic valve tissue from patients with aortic valve stenosis while protein markers of hypoxia were simultaneously increased. Exposure of primary-cultured valve interstitial cells to hypoxia resulted in a decrease in the expression of sFLt-1. We further reveal using a bioassay that siRNA knock-down of sFlt1 in valve interstitial cells directly results in a pro-angiogenic environment. Finally, incubation of aortic valves with sphingosine 1-phosphate, a bioactive lipid-mediator, increased sFlt-1 expression and inhibited angiogenesis within valve tissue. In conclusion, this study demonstrates that sFlt1 expression is directly correlated with angiogenesis in aortic valves and the observed decrease in sFlt-1 expression in aortic valve stenosis could increase valve inflammation, promoting disease progression. This could be a viable therapeutic target in treating this disease.</AbstractText><br /><br />Copyright © 2022. Published by Elsevier Ltd.<br /><br /><small>J Mol Cell Cardiol: 03 Nov 2022; epub ahead of print</small></div>
Lewis CTA, Mascall KS, Wilson HM, Murray F, ... Small GR, Nixon GF
J Mol Cell Cardiol: 03 Nov 2022; epub ahead of print | PMID: 36336008
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Abstract
<div><h4>Generating robust human valvular interstitial cell cultures: Protocol and considerations.</h4><i>Ground M, Park YE, Waqanivavalagi S, Callon K, ... Milsom P, Cornish J</i><br /><AbstractText>Research in heart valve biology is a growing field that has yet to elucidate the fundamentals of valve disease. Human valvular interstitial cells (hVICs) are the best option for studying the cellular mechanisms behind valvular pathologies. However, there is a wide range of isolation procedures for these cells published in the literature. To what extent various isolation methods, patient pathologies, and seeding densities influence the behaviour of hVICs remains unclear. Here, we present an optimised method of hVIC isolation from diseased human valves donated at the time of surgery. We show that two rounds of 1000 U/mL collagenase digestion for not >2 h results in a phenotypically stable cell culture with a near complete absence of endothelial cell contamination. We also suggest that cells should be seeded at 10,000 cells/cm<sup>2</sup> for experimentation. We found that patient pathology does not affect the success of the isolation procedure, and that instead, successful cultures are predicted by ensuring >500 mg valve tissue as starting material.</AbstractText><br /><br />Copyright © 2022 Elsevier Ltd. All rights reserved.<br /><br /><small>J Mol Cell Cardiol: 31 Oct 2022; 173:118-126</small></div>
Ground M, Park YE, Waqanivavalagi S, Callon K, ... Milsom P, Cornish J
J Mol Cell Cardiol: 31 Oct 2022; 173:118-126 | PMID: 36327771
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