Journal: J Mol Cell Cardiol

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Abstract

How to repair a broken heart with pluripotent stem cell-derived cardiomyocytes.

Eschenhagen T, Ridders K, Weinberger F
Heart regeneration addresses a central problem in cardiology, the irreversibility of the loss of myocardium that eventually leads to heart failure. True restoration of heart function can only be achieved by remuscularization, i.e. replacement of lost myocardium by new, force-developing heart muscle. With the availability of principally unlimited human cardiomyocytes from pluripotent stem cells, one option to remuscularize the injured heart is to produce large numbers of cardiomyocytes plus/minus other cardiovascular cell types or progenitors ex vivo and apply them to the heart, either by injection or application as a patch. Exciting progress over the past decade has led to the first clinical applications, but important questions remain. Academic and increasingly corporate activity is ongoing to answer them and optimize the approach to finally develop a true regenerative therapy of heart failure.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 19 Oct 2021; epub ahead of print
Eschenhagen T, Ridders K, Weinberger F
J Mol Cell Cardiol: 19 Oct 2021; epub ahead of print | PMID: 34687723
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Abstract

YAP inhibition promotes endothelial cell differentiation from pluripotent stem cell through EC master transcription factor FLI1.

Quan Y, Shan X, Hu M, Jin P, ... Li M, Wang Y
Endothelial cells (ECs) derived from pluripotent stem cells (PSCs) provide great resource for vascular disease modeling and cell-based regeneration therapy. However, the molecular mechanisms of EC differentiation are not completely understood. In this study, we checked transcriptional profile by microarray and found Hippo pathway is changed and the activity of YAP decreased during mesoderm-mediated EC differentiation from human embryonic stem cells (hESCs). Knockdown of YAP in hESCs promoted both mesoderm and EC differentiation indicating by mesodermal- or EC-specific marker gene expression increased both in mRNA and protein level. In contrast, overexpression of YAP inhibited mesoderm and EC differentiation. Microarray data showed that several key transcription factors of EC differentiation, such as FLI1, ERG, SOX17 are upregulated. Interestingly, knockdown YAP enhanced the expression of these master transcription factors. Bioinformation analysis revealed that TEAD, a YAP binds transcription factors, might regulate the expression of EC master TFs, including FLI1. Luciferase assay confirmed that YAP binds to TEAD1, which would inhibit FLI1 expression. Finally, FLI1 overexpression rescued the effects of YAP overexpression-mediated inhibition of EC differentiation. In conclusion, we revealed the inhibitory effects of YAP on EC differentiation from PSCs, and YAP inhibition might promote expression of master TFs FLI1 for EC commitment through interacting with TEAD1, which might provide an idea for EC differentiation and vascular regeneration via manipulating YAP signaling.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 15 Oct 2021; epub ahead of print
Quan Y, Shan X, Hu M, Jin P, ... Li M, Wang Y
J Mol Cell Cardiol: 15 Oct 2021; epub ahead of print | PMID: 34666000
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Abstract

Krüppel-like factor (KLF)5: An emerging foe of cardiovascular health.

Palioura D, Lazou A, Drosatos K
Krüppel-like factors (KLFs) are DNA-binding transcriptional factors, which regulate various pathways that pertain to development, metabolism and other cellular mechanisms. KLF5 was first cloned in 1993 and by 1999, it was reported as the intestinal-enriched KLF. Beyond findings that have associated KLF5 with normal development and cancer, it has been associated with various types of cardiovascular (CV) complications and regulation of metabolic pathways in the liver, heart, adipose tissue and skeletal muscle. Specifically, increased KLF5 expression has been linked with cardiomyopathy in diabetes, end-stage heart failure, and as well as in vascular atherosclerotic lesions. In this review article, we summarize research findings about transcriptional, post-transcriptional and post-translational regulation of KLF5, as well as the role of KLF5 in the biology of cells and organs that affect cardiovascular health either directly or indirectly. Finally, we propose KLF5 inhibition as an emerging approach for cardiovascular therapeutics.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 11 Oct 2021; epub ahead of print
Palioura D, Lazou A, Drosatos K
J Mol Cell Cardiol: 11 Oct 2021; epub ahead of print | PMID: 34653523
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Abstract

Recapitulation of dyssynchrony-associated contractile impairment in asymmetrically paced engineered heart tissue.

Stenzig J, Lemoine MD, Stoter AMS, Wrona KM, ... Eschenhagen T, Hirt MN
Background
One third of heart failure patients exhibit dyssynchronized electromechanical activity of the heart (evidenced by a broad QRS-complex). Cardiac resynchronization therapy (CRT) in the form of biventricular pacing improves cardiac output and clinical outcome of responding patients. Technically demanding and laborious large animal models have been developed to better predict responders of CRT and to investigate molecular mechanisms of dyssynchrony and CRT. The aim of this study was to establish a first humanized in vitro model of dyssynchrony and CRT.
Methods
Cardiomyocytes were differentiated from human induced pluripotent stem cells and cast into a fibrin matrix to produce engineered heart tissue (EHT). EHTs were either field stimulated in their entirety (symmetrically) or excited locally from one end (asymmetrically) or they were allowed to beat spontaneously.
Results
Asymmetrical pacing led to a depolarization wave from one end to the other end which was visualized in human EHT transduced with a fast genetic Ca2+-sensor (GCaMP6f) arguing for dyssynchronous excitation. Symmetrical pacing in contrast led to an instantaneous (synchronized) Ca2+-signal throughout the EHT. To investigate acute and long-term functional effects, spontaneously beating human EHTs (0.5-0.8 Hz) were divided into a non-paced control group, a symmetrically and an asymmetrically paced group, each stimulated at 1 Hz. Symmetrical pacing was clearly superior to asymmetrical pacing or no pacing regarding contractile force both acutely and even more pronounced after weeks of continuous stimulation. Contractile dysfunction that can be evoked by an increased afterload was aggravated in the asymmetrically paced group. Consistent with reports from paced dogs, p38MAPK and CaMKII-abundance was higher under asymmetrical than under symmetrical pacing while pAKT was considerably lower.
Conclusions
This model allows for long-term pacing experiments mimicking electrical dyssynchrony vs. synchrony in vitro. Combined with force measurement and afterload stimulus manipulation, it provides a robust new tool to gain insight into the biology of dyssynchrony and CRT.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 07 Oct 2021; epub ahead of print
Stenzig J, Lemoine MD, Stoter AMS, Wrona KM, ... Eschenhagen T, Hirt MN
J Mol Cell Cardiol: 07 Oct 2021; epub ahead of print | PMID: 34634355
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Abstract

Systems analysis of the mechanisms governing the cardiovascular response to changes in posture and in peripheral demand during exercise.

Jezek F, Randall EB, Carlson BE, Beard DA
Blood flows and pressures throughout the human cardiovascular system are regulated in response to various dynamic perturbations, such as changes to peripheral demands in exercise, rapid changes in posture, or loss of blood from hemorrhage, via the coordinated action of the heart, the vasculature, and autonomic reflexes. To assess how the systemic and pulmonary arterial and venous circulation, the heart, and the baroreflex work together to effect the whole-body responses to these perturbations, we integrated an anatomically-based large-vessel arterial tree model with the TriSeg heart model, models capturing nonlinear characteristics of the large and small veins, and baroreflex-mediated regulation of control vascular tone and cardiac chronotropy and inotropy. The model was identified by matching data on Valsalva maneuver (VM), exercise, and head-up tilt (HUT). Thirty-one parameters were optimized using a custom parameter-fitting tool chain, resulting in an uniquely high-fidelity whole-body human cardiovascular systems model. Because the model captures the effects of exercise and posture changes, it can be used to simulate numerous clinical assessments, such as HUT, the VM, and cardiopulmonary exercise stress testing. The model can also be applied as a framework for representing and simulating individual patients and pathologies. Moreover, it can serve as a framework for integrating multi-scale organ-level models, such as for the heart or the kidneys, into a whole-body model. Here, the model is used to analyze the relative importance of chronotropic, inotropic, and peripheral vascular contributions to the whole-body cardiovascular response to exercise. It is predicted that in normal physiological conditions chronotropy and inotropy make roughly equal contributions to increasing cardiac output and cardiac power output during exercise. Under upright exercise conditions, the nonlinear pressure-volume relationship of the large veins and sympathetic-mediated venous vasoconstriction are both required to maintain preload to achieve physiological exercise levels. The developed modeling framework is built using the open Modelica modeling language and is freely distributed.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 05 Oct 2021; epub ahead of print
Jezek F, Randall EB, Carlson BE, Beard DA
J Mol Cell Cardiol: 05 Oct 2021; epub ahead of print | PMID: 34626617
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Abstract

3D-cardiomics: A spatial transcriptional atlas of the mammalian heart.

Mohenska M, Tan NM, Tokolyi A, Furtado MB, ... Polo JM, Ramialison M
Understanding the spatial gene expression and regulation in the heart is key to uncovering its developmental and physiological processes, during homeostasis and disease. Numerous techniques exist to gain gene expression and regulation information in organs such as the heart, but few utilize intuitive true-to-life three-dimensional representations to analyze and visualise results. Here we combined transcriptomics with 3D-modelling to interrogate spatial gene expression in the mammalian heart. For this, we microdissected and sequenced transcriptome-wide 18 anatomical sections of the adult mouse heart. Our study has unveiled known and novel genes that display complex spatial expression in the heart sub-compartments. We have also created 3D-cardiomics, an interface for spatial transcriptome analysis and visualization that allows the easy exploration of these data in a 3D model of the heart. 3D-cardiomics is accessible from http://3d-cardiomics.erc.monash.edu/.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 04 Oct 2021; epub ahead of print
Mohenska M, Tan NM, Tokolyi A, Furtado MB, ... Polo JM, Ramialison M
J Mol Cell Cardiol: 04 Oct 2021; epub ahead of print | PMID: 34624332
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Abstract

Conditional depletion of the acetyltransferase Tip60 protects against the damaging effects of myocardial infarction.

Wang X, Wan TC, Lauth A, Purdy AL, ... Lough JW, Auchampach JA
Injury from myocardial infarction (MI) and consequent post-MI remodeling is accompanied by massive loss of cardiomyocytes (CM), a cell type critical for contractile function that is for all practical purposes non-regenerable due to its profound state of proliferative senescence. Identification of factors that limit CM survival and/or constrain CM renewal provides potential therapeutic targets. Tip60, a pan-acetyltransferase encoded by the Kat5 gene, has been reported to activate apoptosis as well as multiple anti-proliferative pathways in non-cardiac cells; however, its role in CMs, wherein it is abundantly expressed, remains unknown. Here, using mice containing floxed Kat5 alleles and a tamoxifen-activated Myh6-MerCreMer recombinase transgene, we report that conditional depletion of Tip60 in CMs three days after MI induced by permanent coronary artery ligation greatly improves functional recovery for up to 28 days. This is accompanied by diminished scarring, activation of cell-cycle transit markers in CMs within the infarct border and remote zones, reduced expression of cell-cycle inhibitors pAtm and p27, and reduced apoptosis in the remote regions. These findings implicate Tip60 as a novel, multifactorial target for limiting the damaging effects of ischemic heart disease.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 01 Oct 2021; 163:9-19
Wang X, Wan TC, Lauth A, Purdy AL, ... Lough JW, Auchampach JA
J Mol Cell Cardiol: 01 Oct 2021; 163:9-19 | PMID: 34610340
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Abstract

Prostaglandin E1 attenuates AngII-induced cardiac hypertrophy via EP3 receptor activation and Netrin-1upregulation.

Shen Y, Wang X, Yuan R, Pan X, ... He B, Shen L
Aims
Pathological cardiac hypertrophy induced by activation of the renin-angiotensin-aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect.
Methods and results
Adult male C57 mice were continuously infused with AngII or saline and treated daily with PGE1 or vehicle for two weeks. Neonatal rat cardiomyocytes were cultured to detect AngII-induced hypertrophic responses. We found that PGE1 ameliorated AngII-induced cardiac hypertrophy both in vivo and in vitro. The RNA sequencing (RNA-seq) and expression pattern analysis results suggest that Netrin-1 (Ntn1) is the specific target gene of PGE1. The protective effect of PGE1 was eliminated after knockdown of Ntn1. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PGE1-mediated signaling pathway changes are associated with the mitogen-activated protein kinase (MAPK) pathway. PGE1 suppressed AngII-induced activation of the MAPK signaling pathway, and such an effect was attenuated by Ntn1 knockdown. Blockade of MAPK signaling rescued the phenotype of cardiomyocytes caused by Ntn1 knockdown, indicating that MAPK signaling may act as the downstream effector of Ntn1. Furthermore, inhibition of the E-prostanoid (EP) 3 receptor, as opposed to the EP1, EP2, or EP4 receptor, in cardiomyocytes reversed the effect of PGE1, and activation of EP3 by sulprostone, a specific agonist, mimicked the effect of PGE1.
Conclusion
In conclusion, PGE1 ameliorates AngII-induced cardiac hypertrophy through activation of the EP3 receptor and upregulation of Ntn1, which inhibits the downstream MAPK signaling pathway. Thus, targeting EP3, as well as the Ntn1-MAPK axis, may represent a novel approach for treating pathological cardiac hypertrophy.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 29 Sep 2021; 159:91-104
Shen Y, Wang X, Yuan R, Pan X, ... He B, Shen L
J Mol Cell Cardiol: 29 Sep 2021; 159:91-104 | PMID: 34147480
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Abstract

Inhibition of Interleukin-21 prolongs the survival through the promotion of wound healing after myocardial infarction.

Kubota A, Suto A, Suga K, Iwata A, ... Kobayashi Y, Nakajima H
Ly6Clow macrophages promote scar formation and prevent early infarct expansion after myocardial infarction (MI). Although CD4+ T cells influence the regulation of Ly6Clow macrophages after MI, the mechanism remains largely unknown. Based on the hypothesis that some molecule(s) secreted by CD4+ T cells act on Ly6Clow macrophages, we searched for candidate molecules by focusing on cytokine receptors expressed on Ly6Clow macrophages. Comparing the transcriptome between Ly6Chigh macrophages and Ly6Clow macrophages harvested from the infarcted heart, we found that Ly6Clow macrophages highly expressed the receptor for interleukin (IL)-21, a pleiotropic cytokine which is produced by several types of CD4+ T cells, compared with Ly6Chigh macrophages. Indeed, CD4+ T cells harvested from the infarcted heart produce IL-21 upon stimulation. Importantly, the survival rate and cardiac function after MI were significantly improved in IL-21-deficient (il21-/-) mice compared with those in wild-type (WT) mice. Transcriptome analysis of infarcted heart tissue from WT mice and il21-/- mice at 5 days after MI demonstrated that inflammation is persistent in WT mice compared with il21-/- mice. Consistent with the transcriptome analysis, the number of neutrophils and matrix metalloproteinase (MMP)-9 expression were significantly decreased, whereas the number of Ly6Clow macrophages and MMP-12 expression were significantly increased in il21-/- mice. In addition, collagen deposition and the number of myofibroblasts in the infarcted area were significantly increased in il21-/- mice. Consistently, IL-21 enhanced the apoptosis of Ly6Clow macrophages. Finally, administration of neutralizing IL-21 receptor Fc protein increased the number of Ly6Clow macrophages in the infarcted heart and improved the survival and cardiac function after MI. Thus, IL-21 decreases the survival after MI, possibly through the delay of wound healing by inducing the apoptosis of Ly6Clow macrophages.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 29 Sep 2021; 159:48-61
Kubota A, Suto A, Suga K, Iwata A, ... Kobayashi Y, Nakajima H
J Mol Cell Cardiol: 29 Sep 2021; 159:48-61 | PMID: 34144051
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Abstract

The mechanistic target of rapamycin complex 1 critically regulates the function of mononuclear phagocytes and promotes cardiac remodeling in acute ischemia.

Chen G, Phan V, Luo X, Cao DJ
Monocytes and macrophages are cellular forces that drive and resolve inflammation triggered by acute myocardial ischemia. One of the most important but least understood regulatory mechanisms is how these cells sense cues from the micro-milieu and integrate environmental signals with their response that eventually determines the outcome of myocardial repair. In the current study, we investigated if the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) plays this role. We present evidence that support a robustly activated mTORC1 pathway in monocytes and macrophages in the infarcting myocardium.. Specific mTORC1 inhibition transformed the landscape of cardiac monocytes and macrophages into reparative cells that promoted myocardial healing. As the result, mTORC1 inhibition diminished remodeling and reduced mortality from acute ischemia by 80%. In conclusion, our data suggest a critical role of mTORC1 in regulating the functions of cardiac monocytes and macrophages, and specific mTORC1 inhibition protects the heart from inflammatory injury in acute ischemia. As mTOR/mTORC1 is a master regulator that integrates external signals with cellular responses, the study sheds light on how the cardiac monocytes and macrophages sense and respond to the ischemic environment..

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 29 Sep 2021; 159:62-79
Chen G, Phan V, Luo X, Cao DJ
J Mol Cell Cardiol: 29 Sep 2021; 159:62-79 | PMID: 34139235
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Abstract

Serum response factor deletion 5 regulates phospholamban phosphorylation and calcium uptake.

Woulfe KC, Jeffrey DA, Pires Da Silva J, Wilson CE, ... Miyamoto SD, Sucharov CC
Aims
Pediatric dilated cardiomyopathy (pDCM) is characterized by unique age-dependent molecular mechanisms that include myocellular responses to therapy. We previously showed that pDCM, but not adult DCM patients respond to phosphodiesterase 3 inhibitors (PDE3i) by increasing levels of the second messenger cAMP and consequent phosphorylation of phospholamban (PLN). However, the molecular mechanisms involved in the differential pediatric and adult response to PDE3i are not clear.
Methods and results
Quantification of serum response factor (SRF) isoforms from the left ventricle of explanted hearts showed that PDE3i treatment affects expression of SRF isoforms in pDCM hearts. An SRF isoform lacking exon 5 (SRFdel5) was highly expressed in the hearts of pediatric, but not adult DCM patients treated with PDE3i. To determine the functional consequence of expression of SRFdel5, we overexpressed full length SRF or SRFdel5 in cultured cardiomyocytes with and without adrenergic stimulation. Compared to a control adenovirus, expression of SRFdel5 increased phosphorylation of PLN, negatively affected expression of the phosphatase that promotes dephosphorylation of PLN (PP2Cε), and promoted faster calcium reuptake, whereas expression of full length SRF attenuated calcium reuptake through blunted phosphorylation of PLN.
Conclusions
Taken together, these data indicate that expression of SRFdel5 in pDCM hearts in response to PDE3i contributes to improved function through regulating PLN phosphorylation and thereby calcium reuptake.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 29 Sep 2021; 159:28-37
Woulfe KC, Jeffrey DA, Pires Da Silva J, Wilson CE, ... Miyamoto SD, Sucharov CC
J Mol Cell Cardiol: 29 Sep 2021; 159:28-37 | PMID: 34139234
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Abstract

Systemic iron deficiency does not affect the cardiac iron content and progression of heart failure.

Paterek A, Oknińska M, Chajduk E, Polkowska-Motrenko H, Mączewski M, Mackiewicz U
Chronic heart failure (HF) is often accompanied by systemic iron deficiency (ID). However, effects of ID on cardiac iron status and progression of HF are unknown. To investigate these effects rats underwent LAD ligation to induce post-myocardial infarction HF or sham operation. After 3 weeks the animals from both groups were randomized into three subgroups: control, moderate ID and severe ID+anemia (IDA) by a combination of phlebotomy and low iron diet for 5 weeks. Serum and hepatic iron content were reduced by 55% and 70% (ID) and by 80% and 77% (IDA), respectively, while cardiac iron content was unchanged in HF rats. Changes in expression of all cardiomyocyte iron handling proteins indicating preserved cardiomyocytes iron status in HF and ID/IDA. Contractile function of LV cardiomyocytes, Ca2+ transient amplitude, sarcoplasmic reticulum Ca2+ release and SERCA2a function was augmented by ID and IDA and it was accompanied by an increase in serum catecholamines. Neither ID nor IDA affected left ventricular (LV) systolic or diastolic function or dimensions. To sum up, systemic ID does not result in cardiac ID and does not affect progression of HF and even improves contractile function and Ca2+ handling of isolated LV cardiomyocytes, however, at the cost of increased catecholamine level. This suggests that intravenous iron therapy should be considered as an additional therapeutic option in HF, preventing the increase of catecholaminergic drive with its well-known long-term adverse effects.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 29 Sep 2021; 159:16-27
Paterek A, Oknińska M, Chajduk E, Polkowska-Motrenko H, Mączewski M, Mackiewicz U
J Mol Cell Cardiol: 29 Sep 2021; 159:16-27 | PMID: 34139233
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Abstract

Programmed cell death in aortic aneurysm and dissection: A potential therapeutic target.

Chakraborty A, Li Y, Zhang C, Li Y, LeMaire SA, Shen YH
Rupture of aortic aneurysm and dissection (AAD) remains a leading cause of death. Progressive smooth muscle cell (SMC) loss is a crucial feature of AAD that contributes to aortic dysfunction and degeneration, leading to aortic aneurysm, dissection, and, ultimately, rupture. Understanding the molecular mechanisms of SMC loss and identifying pathways that promote SMC death in AAD are critical for developing an effective pharmacologic therapy to prevent aortic destruction and disease progression. Cell death is controlled by programmed cell death pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Although these pathways share common stimuli and triggers, each type of programmed cell death has unique features and activation pathways. A growing body of evidence supports a critical role for programmed cell death in the pathogenesis of AAD, and inhibitors of various types of programmed cell death represent a promising therapeutic strategy. This review discusses the different types of programmed cell death pathways and their features, induction, contributions to AAD development, and therapeutic potential. We also highlight the clinical significance of programmed cell death for further studies.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 27 Sep 2021; epub ahead of print
Chakraborty A, Li Y, Zhang C, Li Y, LeMaire SA, Shen YH
J Mol Cell Cardiol: 27 Sep 2021; epub ahead of print | PMID: 34597613
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Abstract

Reverse cardio-oncology: Exploring the effects of cardiovascular disease on cancer pathogenesis.

Koelwyn GJ, Aboumsallem JP, Moore KJ, de Boer RA
The field of cardio-oncology has emerged in response to the increased risk of cardiovascular disease (CVD) in patients with cancer. However, recent studies suggest a more complicated CVD-cancer relationship, wherein development of CVD, either prior to or following a cancer diagnosis, can also lead to increased risk of cancer and worse outcomes for patients. In this review, we describe the current evidence base, across epidemiological as well as preclinical studies, which supports the emerging concept of \'reverse-cardio oncology\', or CVD-induced acceleration of cancer pathogenesis.

Copyright © 2018. Published by Elsevier Ltd.

J Mol Cell Cardiol: 24 Sep 2021; epub ahead of print
Koelwyn GJ, Aboumsallem JP, Moore KJ, de Boer RA
J Mol Cell Cardiol: 24 Sep 2021; epub ahead of print | PMID: 34582824
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Abstract

Oxidized LDL but not angiotensin II induces cardiomyocyte hypertrophic responses through the interaction between LOX-1 and AT receptors.

Lin L, Zhou N, Kang L, Wang Q, ... Yang C, Zou Y
It is well known that lectin-like oxidized low-density lipoprotein (ox-LDL) and its receptor LOX-1, angiotensin II (AngII) and its type 1 receptor (AT1-R) play an important role in the development of cardiac hypertrophy. However, the molecular mechanism is not clear. In this study, we found that ox-LDL-induced cardiac hypertrophy was suppressed by inhibition of LOX-1 or AT1-R but not by AngII inhibition. These results suggest that the receptors LOX-1 and AT1-R, rather than AngII, play a key role in the role of ox-LDL. The same results were obtained in mice lacking endogenous AngII and their isolated cardiomyocytes. Ox-LDL but not AngII could induce the binding of LOX-1 and AT1-R; inhibition of LOX-1 or AT1-R but not AngII could abolish the binding of these two receptors. Overexpression of wild type LOX-1 with AT1-R enhanced ox-LDL-induced binding of two receptors and phosphorylation of ERKs, however, transfection of LOX-1 dominant negative mutant (lys266ala / lys267ala) or an AT1-R mutant (glu257ala) not only reduced the binding of two receptors but also inhibited the ERKs phosphorylation. Phosphorylation of ERKs induced by ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by an inhibitor of Gq protein rather than Jak2, Rac1 or RhoA. Genetically, an AT1-R mutant lacking Gq protein coupling ability inhibited ox-LDL induced ERKs phosphorylation. Furthermore, through bimolecular fluorescence complementation analysis, we confirmed that ox-LDL rather than AngII stimulation induced the direct binding of LOX-1 and AT1-R. We conclude that direct binding of LOX-1 and AT1-R and the activation of downstream Gq protein are important mechanisms of ox-LDL-induced cardiomyocyte hypertrophy.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 20 Sep 2021; 162:110-118
Lin L, Zhou N, Kang L, Wang Q, ... Yang C, Zou Y
J Mol Cell Cardiol: 20 Sep 2021; 162:110-118 | PMID: 34555408
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Abstract

Direct coculture of human pluripotent stem cell-derived cardiac progenitor cells with epicardial cells induces cardiomyocyte proliferation and reduces sarcomere organization.

Floy ME, Dunn KK, Mateyka TD, Reichardt IM, Steinberg AB, Palecek SP
Epicardial cells (EpiCs) are necessary for myocardium formation, yet little is known about crosstalk between EpiCs and cardiomyocytes (CMs) during development and the potential impact of EpiCs on CM maturation. To investigate the effects of EpiCs on CM commitment and maturation, we differentiated human pluripotent stem cells (hPSCs) to cardiac progenitor cells (CPCs) and EpiCs, and cocultured EpiCs and CPCs for two weeks. When EpiCs were allowed to form epicardial-derived cells, we observed increased expression of cTnI in developing CMs. In the presence of the TGFβ inhibitor A83-01, EpiCs remained in the epicardial state and induced CM proliferation, increased MLC2v expression, and led to less organized sarcomeres. These effects were not observed if CPCs were treated with EpiC-conditioned medium or if CPCs were indirectly cocultured with EpiCs. Finally, single cell RNA sequencing identified that EpiC-CPC coculture had bi-directional effects on transcriptional programs in EpiCs and CMs, and biased EpiC lineages from a SFRP2-enriched population to a DLK1- or C3-enriched population. This work suggests important crosstalk between EpiCs and CMs during differentiation can be used to influence cell fate and improve the ability to generate cardiac cells and tissues for in vitro models and development of cardiac cellular therapies.

Copyright © 2018. Published by Elsevier Ltd.

J Mol Cell Cardiol: 20 Sep 2021; epub ahead of print
Floy ME, Dunn KK, Mateyka TD, Reichardt IM, Steinberg AB, Palecek SP
J Mol Cell Cardiol: 20 Sep 2021; epub ahead of print | PMID: 34560089
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Abstract

Hippo/yes-associated protein signaling functions as a mechanotransducer in regulating vascular homeostasis.

Lv H, Ai D
Cells are constantly exposed to various mechanical forces, including hydrostatic pressure, cyclic stretch, fluid shear stress, and extracellular matrix stiffness. Mechanical cues can be translated into the cell-specific transcriptional process by a cellular mechanic-transducer. Evidence suggests that mechanical signals assist activated intracellular signal transduction pathways and the relative phenotypic adaptation to coordinate cell behavior and disease appropriately. The Hippo/yes-associated protein (YAP) signaling pathway is regulated in response to numerous mechanical stimuli. It plays an important role in the mechanotransduction mechanism, which convert mechanical forces to cascades of molecular signaling to modulate gene expression. This review summarizes the recent findings relevant to the Hippo/YAP pathway-based mechanotransduction in cell behavior and maintaining blood vessels, as well as cardiovascular disease.

Copyright © 2018. Published by Elsevier Ltd.

J Mol Cell Cardiol: 17 Sep 2021; epub ahead of print
Lv H, Ai D
J Mol Cell Cardiol: 17 Sep 2021; epub ahead of print | PMID: 34547259
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Abstract

Cellular heterogeneity and immune microenvironment revealed by single-cell transcriptome in venous malformation and cavernous venous malformation.

Li Y, Yang J, Huang Y, Ge S, ... Jia R, Wang Y
Venous malformation (VM) and cavernous venous malformation (CVM) are two types of vascular malformations. Even if the two diseases are similar in appearance and imaging, the distinct cellular components and signaling pathways between them might help distinguish the two from a molecular perspective. Here, we performed single-cell profiling of 35,245 cells from two VM samples and three CVM samples, with a focus on endothelial cells (ECs), smooth muscle cells (SMCs) and immune microenvironment (IME). Clustering analysis based on differential gene expression unveiled 11 specific cell types, and determined CVM had more SMCs. Re-clustering of ECs and SMCs indicated CVM was dominated by arterial components, while VM is dominated by venous components. Gene set variation analysis suggested the activation of inflammation-related pathways in VM ECs, and upregulation of myogenesis pathway in CVM SMCs. In IME analysis, immune cells were identified to accounted for nearly 30% of the total cell number, including macrophages, monocytes, NK cells, T cells and B cells. Notably, more macrophages and monocytes were discovered in VM, indicating innate immune responses might be more closely related to VM pathogenesis. In addition, angiogenesis pathway was highlighted among the significant pathways of macrophages & monocytes between CVM and VM. In VM, VEGFA was highly expressed in macrophages & monocytes, while its receptors were all abundantly present in ECs. The close interaction of VEGFA on macrophages with its receptors on ECs was also predicted by CellPhoneDB analysis. Our results document cellular composition, significant pathways, and critical IME in CVM and VM development.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 15 Sep 2021; 162:130-143
Li Y, Yang J, Huang Y, Ge S, ... Jia R, Wang Y
J Mol Cell Cardiol: 15 Sep 2021; 162:130-143 | PMID: 34536440
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Abstract

Smooth muscle cell CYB5R3 preserves cardiac and vascular function under chronic hypoxic stress.

Durgin BG, Wood KC, Hahn SA, McMahon B, Baust JJ, Straub AC
Chronic hypoxia is a major driver of cardiovascular complications, including heart failure. The nitric oxide (NO) - soluble guanylyl cyclase (sGC) - cyclic guanosine monophosphate (cGMP) pathway is integral to vascular tone maintenance. Specifically, NO binds its receptor sGC within vascular smooth muscle cells (SMC) in its reduced heme (Fe2+) form to increase intracellular cGMP production, activate protein kinase G (PKG) signaling, and induce vessel relaxation. Under chronic hypoxia, oxidative stress drives oxidation of sGC heme (Fe2+→Fe3+), rendering it NO-insensitive. We previously showed that cytochrome b5 reductase 3 (CYB5R3) in SMC is a sGC reductase important for maintaining NO-dependent vasodilation and conferring resilience to systemic hypertension and sickle cell disease-associated pulmonary hypertension. To test whether CYB5R3 may be protective in the context of chronic hypoxia, we subjected SMC-specific CYB5R3 knockout mice (SMC CYB5R3 KO) to 3 weeks hypoxia and assessed vascular and cardiac function using echocardiography, pressure volume loops and wire myography. Hypoxic stress caused 1) biventricular hypertrophy in both WT and SMC CYB5R3 KO, but to a larger degree in KO mice, 2) blunted vasodilation to NO-dependent activation of sGC in coronary and pulmonary arteries of KO mice, and 3) decreased, albeit still normal, cardiac function in KO mice. Overall, these data indicate that SMC CYB5R3 deficiency potentiates bilateral ventricular hypertrophy and blunts NO-dependent vasodilation under chronic hypoxia conditions. This implicates that SMC CYB5R3 KO mice post 3-week hypoxia have early stages of cardiac remodeling and functional changes that could foretell significantly impaired cardiac function with longer exposure to hypoxia.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 14 Sep 2021; 162:72-80
Durgin BG, Wood KC, Hahn SA, McMahon B, Baust JJ, Straub AC
J Mol Cell Cardiol: 14 Sep 2021; 162:72-80 | PMID: 34536439
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Abstract

Interaction of SOX5 with SOX9 promotes warfarin-induced aortic valve interstitial cell calcification by repressing transcriptional activation of LRP6.

Qiu M, Lu Y, Li J, Gu J, ... Kong X, Sun W
Calcific aortic valve disease (CAVD) is an important health burden due to its increasing prevalence and lack of available approaches. Osteogenic transdifferentiation of aortic valve interstitial cells (AVICs) contributes to valve calcification. SRY-related HMG-box transcription factor 5 (SOX5) is essential for cartilage development. Whether SOX5 is involved in AVIC calcification has not been determined. This study aimed to explore the role of SOX5 in warfarin-induced AVIC calcification. Immunostaining showed decreased SOX5 in human calcific AV and warfarin induced mouse calcific AV tissues compared with human noncalcific AV and control mouse AV tissues. In calcific human AVICs (hAVICs) and porcine AVICS (pAVICs), both knockdown and overexpression of SOX5 inhibited calcium deposition and osteogenic marker gene expression. Protein expression assays and ChIP assays showed that overexpression of SOX5 led to increased recruitment of SOX5 to the SOX9 promoter and resulted in increased mRNA and protein expression of SOX9. Coimmunoprecipitation and immunofluorescence showed that SOX5 binds to SOX9 with its HMG domain in nucleus. Blue Native PAGE showed overexpression of SOX5 led to multimeric complex formation of SOX5 and resulted in decreased binding of SOX5 to SOX9 similar to the results of knockdown of SOX5. Further ChIP and western blotting assays showed that both knockdown and overexpression of SOX5 resulted in SOX9 initiating transcription of anti-calcific gene LRP6 in warfarin-treated pAVICs. Knockdown of LRP6 rescues the anti-calcification effect of SOX5 overexpression. We found that both loss and gain of function of SOX5 lead to the same phenotype: decreased warfarin induced calcification. The stoichiometry of SOX5 is crucial for cooperation with SOX9, SOX9 nuclear localization and subsequent binding of SOX9 to LRP6 promoter. These results suggest that SOX5 is a potential target for the development of anti-calcification therapy.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 10 Sep 2021; 162:81-96
Qiu M, Lu Y, Li J, Gu J, ... Kong X, Sun W
J Mol Cell Cardiol: 10 Sep 2021; 162:81-96 | PMID: 34520801
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Abstract

Delineating chromatin accessibility re-patterning at single cell level during early stage of direct cardiac reprogramming.

Wang H, Yang Y, Qian Y, Liu J, Qian L
Direct conversion of cardiac fibroblast into induced cardiomyocytes (iCMs) by forced expression of cardiac transcription factors, such as Mef2c, Gata4, and Tbx5 (MGT), holds great promise for regenerative medicine. The process of cardiac reprogramming consists of waves of transcriptome remodelling events. However, how this transcriptome remodelling is driven by the upstream chromatin landscape alteration is still unclear. In this study, we performed single-cell ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) on early reprogramming iCMs given the known epigenetic changes as early as day 3. This approach unveiled networks of transcription factors (TFs) involved in the early shift of chromatin accessibility during cardiac reprogramming. Combining our analysis with functional assays, we identified Smad3 to be a bimodal TF in cardiac reprogramming, a barrier in the initiation of reprogramming and a facilitator during the intermediate stage of reprogramming. Moreover, integrative analysis of scATAC-seq with scRNA-seq data led to the identification of active TFs important for iCM conversion. Finally, we discovered a global rewiring of cis-regulatory interactions of cardiac genes along the reprogramming trajectory. Collectively, our scATAC-seq study and the integrative analysis with scRNA-seq data provided valuable resources to understand the epigenomic heterogeneity and its alteration in relation to transcription changes during early stage of cardiac reprogramming.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 09 Sep 2021; 162:62-71
Wang H, Yang Y, Qian Y, Liu J, Qian L
J Mol Cell Cardiol: 09 Sep 2021; 162:62-71 | PMID: 34509499
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Abstract

Histone deacetylase 4 deletion broadly affects cardiac epigenetic repression and regulates transcriptional susceptibility via H3K9 methylation.

Finke D, Schanze LM, Schreiter F, Kreußer MM, ... Backs J, Lehmann LH
Histone deacetylase 4 (HDAC4) is a member of class IIa histone deacetylases (class IIa HDACs) and is believed to possess a low intrinsic deacetylase activity. However, HDAC4 sufficiently represses distinct transcription factors (TFs) such as the myocyte enhancer factor 2 (MEF2). Transcriptional repression by HDAC4 has been suggested to be mediated by the recruitment of other chromatin-modifying enzymes, such as methyltransferases or class I histone deacetylases. However, this concept has not been investigated by an unbiased approach. Therefore, we studied the histone modifications H3K4me3, H3K9ac, H3K27ac, H3K9me2 and H3K27me3 in a genome-wide approach using HDAC4-deficient cardiomyocytes. We identified a general epigenetic shift from a \'repressive\' to an \'active\' status, characterized by an increase of H3K4me3, H3K9ac and H3K27ac and a decrease of H3K9me2 and H3K27me3. In HDAC4-deficient cardiomyocytes, MEF2 binding sites were considerably overrepresented in upregulated promoter regions of H3K9ac and H3K4me3. For example, we identified the promoter of Adprhl1 as a new genomic target of HDAC4 and MEF2. Overexpression of HDAC4 in cardiomyocytes was able to repress the transcription of the Adprhl1 promoter in the presence of the methyltransferase SUV39H1. On a genome-wide level, the decrease of H3K9 methylation did not change baseline expression but was associated with exercise-induced gene expression. We conclude that HDAC4, on the one hand, associates with activating histone modifications, such as H3K4me3 and H3K9ac. A functional consequence, on the other hand, requires an indirect regulation of H3K9me2. H3K9 hypomethylation in HDAC4 target genes (\'first hit\') plus a \'second hit\' (e.g., exercise) determines the transcriptional response.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 03 Sep 2021; 162:119-129
Finke D, Schanze LM, Schreiter F, Kreußer MM, ... Backs J, Lehmann LH
J Mol Cell Cardiol: 03 Sep 2021; 162:119-129 | PMID: 34492228
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Abstract

Myofilament glycation in diabetes reduces contractility by inhibiting tropomyosin movement, is rescued by cMyBPC domains.

Papadaki M, Kampaengsri T, Barrick SK, Campbell SG, ... Greenberg MJ, Kirk JA
Diabetes doubles the risk of developing heart failure (HF). As the prevalence of diabetes grows, so will HF unless the mechanisms connecting these diseases can be identified. Methylglyoxal (MG) is a glycolysis by-product that forms irreversible modifications on lysine and arginine, called glycation. We previously found that myofilament MG glycation causes sarcomere contractile dysfunction and is increased in patients with diabetes and HF. The aim of this study was to discover the molecular mechanisms by which MG glycation of myofilament proteins cause sarcomere dysfunction and to identify therapeutic avenues to compensate. In humans with type 2 diabetes without HF, we found increased glycation of sarcomeric actin compared to non-diabetics and it correlated with decreased calcium sensitivity. Depressed calcium sensitivity is pathogenic for HF, therefore myofilament glycation represents a promising therapeutic target to inhibit the development of HF in diabetics. To identify possible therapeutic targets, we further defined the molecular actions of myofilament glycation. Skinned myocytes exposed to 100 μM MG exhibited decreased calcium sensitivity, maximal calcium-activated force, and crossbridge kinetics. Replicating MG\'s functional affects using a computer simulation of sarcomere function predicted simultaneous decreases in tropomyosin\'s blocked-to-closed rate transition and crossbridge duty cycle were consistent with all experimental findings. Stopped-flow experiments and ATPase activity confirmed MG decreased the blocked-to-closed transition rate. Currently, no therapeutics target tropomyosin, so as proof-of-principal, we used a n-terminal peptide of myosin-binding protein C, previously shown to alter tropomyosin\'s position on actin. C0C2 completely rescued MG-induced calcium desensitization, suggesting a possible treatment for diabetic HF.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 02 Sep 2021; 162:1-9
Papadaki M, Kampaengsri T, Barrick SK, Campbell SG, ... Greenberg MJ, Kirk JA
J Mol Cell Cardiol: 02 Sep 2021; 162:1-9 | PMID: 34487755
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Abstract

In vivo deep network tracing reveals phosphofructokinase-mediated coordination of biosynthetic pathway activity in the myocardium.

Fulghum KL, Audam TN, Lorkiewicz PK, Zheng Y, ... Fan TWM, Hill BG
Glucose metabolism comprises numerous amphibolic metabolites that provide precursors for not only the synthesis of cellular building blocks but also for ATP production. In this study, we tested how phosphofructokinase-1 (PFK1) activity controls the fate of glucose-derived carbon in murine hearts in vivo. PFK1 activity was regulated by cardiac-specific overexpression of kinase- or phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgenes in mice (termed GlycoLo or GlycoHi mice, respectively). Dietary delivery of 13C6-glucose to these mice, followed by deep network metabolic tracing, revealed that low rates of PFK1 activity promote selective routing of glucose-derived carbon to the purine synthesis pathway to form 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Consistent with a mechanism of physical channeling, we found multimeric protein complexes that contained phosphoribosylaminoimidazole carboxylase (PAICS)-an enzyme important for AICAR biosynthesis, as well as chaperone proteins such as Hsp90 and other metabolic enzymes. We also observed that PFK1 influenced glucose-derived carbon deposition in glycogen, but did not affect hexosamine biosynthetic pathway activity. These studies demonstrate the utility of deep network tracing to identify metabolic channeling and changes in biosynthetic pathway activity in the heart in vivo and present new potential mechanisms by which metabolic branchpoint reactions modulate biosynthetic pathways.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 02 Sep 2021; 162:32-42
Fulghum KL, Audam TN, Lorkiewicz PK, Zheng Y, ... Fan TWM, Hill BG
J Mol Cell Cardiol: 02 Sep 2021; 162:32-42 | PMID: 34487754
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Abstract

Computational modeling of aberrant electrical activity following remuscularization with intramyocardially injected pluripotent stem cell-derived cardiomyocytes.

Yu JK, Liang JA, Weinberg SH, Trayanova NA
Acute engraftment arrhythmias (EAs) remain a serious complication of remuscularization therapy. Preliminary evidence suggests that a focal source underlies these EAs stemming from the automaticity of immature pluripotent stem cell-derived cardiomyocytes (PSC-CMs) in nascent myocardial grafts. How these EAs arise though during early engraftment remains unclear. In a series of in silico experiments, we probed the origin of EAs-exploring aspects of altered impulse formation and altered impulse propagation within nascent PSC-CM grafts and at the host-graft interface. To account for poor gap junctional coupling during early PSC-CM engraftment, the voltage dependence of gap junctions and the possibility of ephaptic coupling were incorporated. Inspired by cardiac development, we also studied the contributions of another feature of immature PSC-CMs, circumferential sodium channel (NaCh) distribution in PSC-CMs. Ectopic propagations emerged from nascent grafts of immature PSC-CMs at a rate of <96 bpm. Source-sink effects dictated this rate and contributed to intermittent capture between host and graft. Moreover, ectopic beats emerged from dynamically changing sites along the host-graft interface. The latter arose in part because circumferential NaCh distribution in PSC-CMs contributed to preferential conduction slowing and block of electrical impulses from host to graft myocardium. We conclude that additional mechanisms, in addition to focal ones, contribute to EAs and recognize that their relative contributions are dynamic across the engraftment process.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 02 Sep 2021; 162:97-109
Yu JK, Liang JA, Weinberg SH, Trayanova NA
J Mol Cell Cardiol: 02 Sep 2021; 162:97-109 | PMID: 34487753
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Abstract

Exosomes from adipose-derived stem cells alleviate myocardial infarction via microRNA-31/FIH1/HIF-1α pathway.

Zhu D, Wang Y, Thomas M, McLaughlin K, ... Chen YE, Liu D
Our previous study has revealed that exosomes from adipose-derived stem cells (ASCs) promote angiogenesis in subcutaneously transplanted gels by delivery of microRNA-31 (miR-31) which targets factor inhibiting hypoxia-inducible factor-1 (FIH1) in recipient cells. Here we hypothesized that ASC exosomes alleviate ischemic diseases through miR-31/FIH1/hypoxia-inducible factor-1α (HIF-1α) signaling pathway. Exosomes from ASCs were characterized with nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting analysis for exosomal markers. Results from immunoblotting and laser imaging of ischemic mouse hindlimb revealed that miR-31 enriched ASC exosomes inhibited FIH1 expression and enhanced the blood perfusion, respectively. These effects were impaired when using miR-31-depleted exosomes. Immunohistochemistry analysis showed that administration of exosomes resulted in a higher arteriole density and larger CD31+ area in ischemic hindlimb than miR-31-delpleted exosomes. Similarly, knockdown of miR-31 in exosomes reduced the effects of the exosomes on increasing ventricular fraction shortening and CD31+ area, and on decreasing infarct size. Exosomes promoted endothelial cell migration and tube formation. These changes were attenuated when miR-31 was depleted in the exosomes or when FIH1 was overexpressed in the endothelial cells. Furthermore, the results from immunocytochemistry, co-immunoprecipitation, and luciferase reporter assay demonstrated that the effects of exosomes on nuclear translocation, binding with co-activator p300, and activation of HIF-1α were decreased when miR-31 was depleted in the exosomes or FIH1 was overexpressed. Our findings provide evidence that exosomes from ASCs promote angiogenesis in both mouse ischemic hindlimb and heart through transport of miR-31 which targets FIH1 and therefore triggers HIF-1α transcriptional activation.

Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 29 Aug 2021; 162:10-19
Zhu D, Wang Y, Thomas M, McLaughlin K, ... Chen YE, Liu D
J Mol Cell Cardiol: 29 Aug 2021; 162:10-19 | PMID: 34474073
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Abstract

Bottom-up proteomic analysis of human adult cardiac tissue and isolated cardiomyocytes.

Wojtkiewicz M, Berg Luecke L, Castro C, Burkovetskaya M, Mesidor R, Gundry RL
The heart is composed of multiple cell types, each with a specific function. Cell-type-specific approaches are necessary for defining the intricate molecular mechanisms underlying cardiac development, homeostasis, and pathology. While single-cell RNA-seq studies are beginning to define the chamber-specific cellular composition of the heart, our views of the proteome are more limited because most proteomics studies have utilized homogenized human cardiac tissue. To promote future cell-type specific analyses of the human heart, we describe the first method for cardiomyocyte isolation from cryopreserved human cardiac tissue followed by flow cytometry for purity assessment. We also describe a facile method for preparing isolated cardiomyocytes and whole cardiac tissue homogenate for bottom-up proteomic analyses. Prior experience in dissociating cardiac tissue or proteomics is not required to execute these methods. We compare different sample preparation workflows and analysis methods to demonstrate how these can impact the depth of proteome coverage achieved. We expect this how-to guide will serve as a starting point for investigators interested in general and cell-type-specific views of the cardiac proteome.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 23 Aug 2021; 162:20-31
Wojtkiewicz M, Berg Luecke L, Castro C, Burkovetskaya M, Mesidor R, Gundry RL
J Mol Cell Cardiol: 23 Aug 2021; 162:20-31 | PMID: 34437879
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Abstract

Targeting senescent cells for vascular aging and related diseases.

Ding YN, Wang HY, Chen HZ, Liu DP
Cardiovascular diseases are a serious threat to human health, especially in the elderly. Vascular aging makes people more susceptible to cardiovascular diseases due to significant dysfunction or senescence of vascular cells and maladaptation of vascular structure and function; moreover, vascular aging is currently viewed as a modifiable cardiovascular risk factor. To emphasize the relationship between senescent cells and vascular aging, we first summarize the roles of senescent vascular cells (endothelial cells, smooth muscle cells and immune cells) in the vascular aging process and inducers that contribute to cellular senescence. Then, we present potential strategies for directly targeting senescent cells (senotherapy) or preventively targeting senescence inducers (senoprevention) to delay vascular aging and the development of age-related vascular diseases. Finally, based on recent research, we note some important questions that still need to be addressed in the future.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 22 Aug 2021; 162:43-52
Ding YN, Wang HY, Chen HZ, Liu DP
J Mol Cell Cardiol: 22 Aug 2021; 162:43-52 | PMID: 34437878
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Abstract

Post-translational modifications talk and crosstalk to class IIa histone deacetylases.

Guttzeit S, Backs J
Epigenetic modifications, such as histone or DNA modifications are key regulators of gene transcription and changes are often associated with maladaptive processes underlying cardiovascular disease. Epigenetic regulators therefore likely play a crucial role in cardiomyocyte homeostasis and facilitate the cellular adaption to various internal and external stimuli, responding to different intercellular and extracellular cues. Class IIa histone deacetylases are a class of epigenetic regulators that possess a myriad of post-transcriptional modification sites that modulate their activity in response to oxidative stress, altered catecholamine signalling or changes in the cellular metabolism. This review summaries the known reversible, post-translational modifications (PTMs) of class IIa histone deacetylases (HDACs) that ultimately drive transcriptional changes in homeostasis and disease. We also highlight the idea of a crosstalk of various PTMs on class IIa HDACs potentially leading to compensatory or synergistic effects on the class IIa HDAC-regulated cell behavior.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 16 Aug 2021; 162:53-61
Guttzeit S, Backs J
J Mol Cell Cardiol: 16 Aug 2021; 162:53-61 | PMID: 34416247
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Abstract

Triiodothyronine and dexamethasone alter potassium channel expression and promote electrophysiological maturation of human-induced pluripotent stem cell-derived cardiomyocytes.

Wang L, Wada Y, Ballan N, Schmeckpeper J, ... Gepstein L, Knollmann BC
Background
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising tool for disease modeling and drug development. However, hiPSC-CMs remain functionally immature, which hinders their utility as a model of human cardiomyocytes.
Objective
To improve the electrophysiological maturation of hiPSC-CMs.
Methods and results
On day 16 of cardiac differentiation, hiPSC-CMs were treated with 100 nmol/L triiodothyronine (T3) and 1 μmol/L Dexamethasone (Dex) or vehicle for 14 days. On day 30, vehicle- and T3 + Dex-treated hiPSC-CMs were dissociated and replated either as cell sheets or single cells. Optical mapping and patch-clamp technique were used to examine the electrophysiological properties of vehicle- and T3 + Dex-treated hiPSC-CMs. Compared to vehicle, T3 + Dex-treated hiPSC-CMs had a slower spontaneous beating rate, more hyperpolarized resting membrane potential, faster maximal upstroke velocity, and shorter action potential duration. Changes in spontaneous activity and action potential were mediated by decreased hyperpolarization-activated current (If) and increased inward rectifier potassium currents (IK1), sodium currents (INa), and the rapidly and slowly activating delayed rectifier potassium currents (IKr and IKs, respectively). Furthermore, T3 + Dex-treated hiPSC-CM cell sheets (hiPSC-CCSs) exhibited a faster conduction velocity and shorter action potential duration than the vehicle. Inhibition of IK1 by 100 μM BaCl2 significantly slowed conduction velocity and prolonged action potential duration in T3 + Dex-treated hiPSC-CCSs but had no effect in the vehicle group, demonstrating the importance of IK1 for conduction velocity and action potential duration.
Conclusion
T3 + Dex treatment is an effective approach to rapidly enhance electrophysiological maturation of hiPSC-CMs.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 12 Aug 2021; 161:130-138
Wang L, Wada Y, Ballan N, Schmeckpeper J, ... Gepstein L, Knollmann BC
J Mol Cell Cardiol: 12 Aug 2021; 161:130-138 | PMID: 34400182
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Abstract

MITOL/MARCH5 determines the susceptibility of cardiomyocytes to doxorubicin-induced ferroptosis by regulating GSH homeostasis.

Kitakata H, Endo J, Matsushima H, Yamamoto S, ... Fukuda K, Sano M
MITOL/MARCH5 is an E3 ubiquitin ligase that plays a crucial role in the control of mitochondrial quality and function. However, the significance of MITOL in cardiomyocytes under physiological and pathological conditions remains unclear. First, to determine the significance of MITOL in unstressed hearts, we assessed the cellular changes with the reduction of MITOL expression by siRNA in neonatal rat primary ventricular cardiomyocytes (NRVMs). MITOL knockdown in NRVMs induced cell death via ferroptosis, a newly defined non-apoptotic programmed cell death, even under no stress conditions. This phenomenon was observed only in NRVMs, not in other cell types. MITOL knockdown markedly reduced mitochondria-localized GPX4, a key enzyme associated with ferroptosis, promoting accumulation of lipid peroxides in mitochondria. In contrast, the activation of GPX4 in MITOL knockdown cells suppressed lipid peroxidation and cell death. MITOL knockdown reduced the glutathione/oxidized glutathione (GSH/GSSG) ratio that regulated GPX4 expression. Indeed, the administration of GSH or N-acetylcysteine improved the expression of GPX4 and viability in MITOL-knockdown NRVMs. MITOL-knockdown increased the expression of the glutathione-degrading enzyme, ChaC glutathione-specific γ-glutamylcyclotransferase 1 (Chac1). The knockdown of Chac1 restored the GSH/GSSG ratio, GPX4 expression, and viability in MITOL-knockdown NRVMs. Further, in cultured cardiomyocytes stressed with DOX, both MITOL and GPX4 were reduced, whereas forced-expression of MITOL suppressed DOX-induced ferroptosis by maintaining GPX4 content. Additionally, MITOL knockdown worsened vulnerability to DOX, which was almost completely rescued by treatment with ferrostatin-1, a ferroptosis inhibitor. In vivo, cardiac-specific depletion of MITOL did not produce obvious abnormality, but enhanced susceptibility to DOX toxicity. Finally, administration of ferrostatin-1 suppressed exacerbation of DOX-induced myocardial damage in MITOL-knockout hearts. The present study demonstrates that MITOL determines the cell fate of cardiomyocytes via the ferroptosis process and plays a key role in regulating vulnerability to DOX treatment. (288/300).

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 11 Aug 2021; 161:116-129
Kitakata H, Endo J, Matsushima H, Yamamoto S, ... Fukuda K, Sano M
J Mol Cell Cardiol: 11 Aug 2021; 161:116-129 | PMID: 34390730
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Abstract

MyD88: At the heart of inflammatory signaling and cardiovascular disease.

Bayer AL, Alcaide P
Cardiovascular disease is a leading cause of death worldwide and is associated with systemic inflammation. In depth study of the cell-specific signaling mechanisms mediating the inflammatory response is vital to improving anti-inflammatory therapies that reduce mortality and morbidity. Cellular damage in the cardiovascular system results in the release of damage associated molecular patterns (DAMPs), also known as \"alarmins,\" which activate myeloid cells through the adaptor protein myeloid differentiation primary response 88 (MyD88). MyD88 is broadly expressed in most cell types of the immune and cardiovascular systems, and its role often differs in a cardiovascular disease context and cell specific manner. Herein we review what is known about MyD88 in the setting of a variety of cardiovascular diseases, discussing cell specific functions and the relative contributions of MyD88-dependent vs. independent alarmin triggered inflammatory signaling. The widespread involvement of these pathways in cardiovascular disease, and their largely unexplored complexity, sets the stage for future in depth mechanistic studies that may place MyD88 in both immune and non-immune cell types as an attractive target for therapeutic intervention in cardiovascular disease.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 07 Aug 2021; 161:75-85
Bayer AL, Alcaide P
J Mol Cell Cardiol: 07 Aug 2021; 161:75-85 | PMID: 34371036
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Abstract

CaMKIIδ post-translational modifications increase affinity for calmodulin inside cardiac ventricular myocytes.

Simon M, Ko CY, Rebbeck RT, Baidar S, Cornea RL, Bers DM
Persistent over-activation of CaMKII (Calcium/Calmodulin-dependent protein Kinase II) in the heart is implicated in arrhythmias, heart failure, pathological remodeling, and other cardiovascular diseases. Several post-translational modifications (PTMs)-including autophosphorylation, oxidation, S-nitrosylation, and O-GlcNAcylation-have been shown to trap CaMKII in an autonomously active state. The molecular mechanisms by which these PTMs regulate calmodulin (CaM) binding to CaMKIIδ-the primary cardiac isoform-has not been well-studied particularly in its native myocyte environment. Typically, CaMKII activates upon Ca-CaM binding during locally elevated [Ca]free and deactivates upon Ca-CaM dissociation when [Ca]free returns to basal levels. To assess the effects of CaMKIIδ PTMs on CaM binding, we developed a novel FRET (Förster resonance energy transfer) approach to directly measure CaM binding to and dissociation from CaMKIIδ in live cardiac myocytes. We demonstrate that autophosphorylation of CaMKIIδ increases affinity for CaM in its native environment and that this increase is dependent on [Ca]free. This leads to a 3-fold slowing of CaM dissociation from CaMKIIδ (time constant slows from ~0.5 to 1.5 s) when [Ca]free is reduced with physiological kinetics. Moreover, oxidation further slows CaM dissociation from CaMKIIδ T287D (phosphomimetic) upon rapid [Ca]free chelation and increases FRET between CaM and CaMKIIδ T287A (phosphoresistant). The CaM dissociation kinetics-measured here in myocytes-are similar to the interval between heartbeats, and integrative memory would be expected as a function of heart rate. Furthermore, the PTM-induced slowing of dissociation between beats would greatly promote persistent CaMKIIδ activity in the heart. Together, these findings suggest a significant role of PTM-induced changes in CaMKIIδ affinity for CaM and memory under physiological and pathophysiological processes in the heart.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

J Mol Cell Cardiol: 07 Aug 2021; 161:53-61
Simon M, Ko CY, Rebbeck RT, Baidar S, Cornea RL, Bers DM
J Mol Cell Cardiol: 07 Aug 2021; 161:53-61 | PMID: 34371035
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Abstract

With a grain of salt: Sodium elevation and metabolic remodelling in heart failure.

Aksentijević D, Shattock MJ
Elevated intracellular Na (Nai) and metabolic impairment are interrelated pathophysiological features of the failing heart (HF). There have been a number of studies showing that myocardial sodium elevation subtly affects mitochondrial function. During contraction, mitochondrial calcium (Camito) stimulates a variety of TCA cycle enzymes, thereby providing reducing equivalents to maintain ATP supply. Nai elevation has been shown to impact Camito; however, whether metabolic remodelling in HF is caused by increased Nai has only been recently demonstrated. This novel insight may help to elucidate the contribution of metabolic remodelling in the pathophysiology of HF, the lack of efficacy of current HF therapies and a rationale for the development of future metabolism-targeting treatments. Here we review the relationship between Na pump inhibition, elevated Nai, and altered metabolic profile in the context of HF and their link to metabolic (in)flexibility and mitochondrial reprogramming.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 07 Aug 2021; 161:106-115
Aksentijević D, Shattock MJ
J Mol Cell Cardiol: 07 Aug 2021; 161:106-115 | PMID: 34371034
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Abstract

Selective activation of adrenoceptors potentiates I current in pulmonary vein cardiomyocytes through the protein kinase A and C signaling pathways.

Mi X, Ding WG, Toyoda F, Kojima A, Omatsu-Kanbe M, Matsuura H
Delayed rectifier K+ current (IKs) is a key contributor to repolarization of action potentials. This study investigated the mechanisms underlying the adrenoceptor-induced potentiation of IKs in pulmonary vein cardiomyocytes (PVC). PVC were isolated from guinea pig pulmonary vein. The action potentials and IKs current were recorded using perforated and conventional whole-cell patch-clamp techniques. The expression of IKs was examined using immunocytochemistry and Western blotting. KCNQ1, a IKs pore-forming protein was detected as a signal band approximately 100 kDa in size, and its immunofluorescence signal was found to be mainly localized on the cell membrane. The IKs current in PVC was markedly enhanced by both β1- and β2-adrenoceptor stimulation with a negative voltage shift in the current activation, although the potentiation was more effectively induced by β2-adrenoceptor stimulation than β1-adrenoceptor stimulation. Both β-adrenoceptor-mediated increases in IKs were attenuated by treatment with the adenylyl cyclase (AC) inhibitor or protein kinase A (PKA) inhibitor. Furthermore, the IKs current was increased by α1-adrenoceptor agonist but attenuated by the protein kinase C (PKC) inhibitor. PVC exhibited action potentials in normal Tyrode solution which was slightly reduced by HMR-1556 a selective IKs blocker. However, HMR-1556 markedly reduced the β-adrenoceptor-potentiated firing rate. The stimulatory effects of β- and α1-adrenoceptor on IKs in PVC are mediated via the PKA and PKC signal pathways. HMR-1556 effectively reduced the firing rate under β-adrenoceptor activation, suggesting that the functional role of IKs might increase during sympathetic excitation under in vivo conditions.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 07 Aug 2021; 161:86-97
Mi X, Ding WG, Toyoda F, Kojima A, Omatsu-Kanbe M, Matsuura H
J Mol Cell Cardiol: 07 Aug 2021; 161:86-97 | PMID: 34375616
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Abstract

MicroRNA-663 prevents monocrotaline-induced pulmonary arterial hypertension by targeting TGF-β1/smad2/3 signaling.

Li P, Song J, Du H, Lu Y, ... Qin Y, Zhu N
Objective
Pulmonary vascular remodeling due to excessive growth factor production and pulmonary artery smooth muscle cells (PASMCs) proliferation is the hallmark feature of pulmonary arterial hypertension (PAH). Recent studies suggest that miR-663 is a potent modulator for tumorigenesis and atherosclerosis. However, whether miR-663 involves in pulmonary vascular remodeling is still unclear.
Methods and results
By using quantitative RT-PCR, we found that miR-663 was highly expressed in normal human PASMCs. In contrast, circulating level of miR-663 dramatically reduced in PAH patients. In addition, in situ hybridization showed that expression of miR-663 was decreased in pulmonary vasculature of PAH patients. Furthermore, MTT and cell scratch-wound assay showed that transfection of miR-663 mimics significantly inhibited platelet derived growth factor (PDGF)-induced PASMCs proliferation and migration, while knockdown of miR-663 expression enhanced these effects. Mechanistically, dual-luciferase reporter assay revealed that miR-663 directly targets the 3\'UTR of TGF-β1. Moreover, western blots and ELISA results showed that miR-663 decreased PDGF-induced TGF-β1 expression and secretion, which in turn suppressed the downstream smad2/3 phosphorylation and collagen I expression. Finally, intratracheal instillation of adeno-miR-663 efficiently inhibited the development of pulmonary vascular remodeling and right ventricular hypertrophy in monocrotaline (MCT)-induced PAH rat models.
Conclusion
These results indicate that miR-663 is a potential biomarker for PAH. MiR-663 decreases PDGF-BB-induced PASMCs proliferation and prevents pulmonary vascular remodeling and right ventricular hypertrophy in MCT-PAH by targeting TGF-β1/smad2/3 signaling. These findings suggest that miR-663 may represent as an attractive approach for the diagnosis and treatment for PAH.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 30 Jul 2021; 161:9-22
Li P, Song J, Du H, Lu Y, ... Qin Y, Zhu N
J Mol Cell Cardiol: 30 Jul 2021; 161:9-22 | PMID: 34339758
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Abstract

ILF3 is responsible for hyperlipidemia-induced arteriosclerotic calcification by mediating BMP2 and STAT1 transcription.

Xie F, Cui QK, Wang ZY, Liu B, ... Wang Y, Zhang MX
Calcification is common in atherosclerotic plaque and can induce vulnerability, which further leads to myocardial infarction, plaque rupture and stroke. The mechanisms of atherosclerotic calcification are poorly characterized. Interleukin enhancer binding factor 3 (ILF3) has been identified as a novel factor affecting dyslipidemia and stroke subtypes. However, the precise role of ILF3 in atherosclerotic calcification remains unclear. In this study, we used smooth muscle-conditional ILF3 knockout (ILF3SM-KO) and transgenic mice (ILF3SM-Tg) and macrophage-conditional ILF3 knockout (ILF3M-KO) and transgenic (ILF3M-Tg) mice respectively. Here we showed that ILF3 expression is increased in calcified human aortic vascular smooth muscle cells (HAVSMCs) and calcified atherosclerotic plaque in humans and mice. We then found that hyperlipidemia increases ILF3 expression and exacerbates calcification of VSMCs and macrophages by regulating bone morphogenetic protein 2 (BMP2) and signal transducer and activator of transcription 1 (STAT1) transcription. We further explored the molecular mechanisms of ILF3 in atherosclerotic calcification and revealed that ILF3 acts on the promoter regions of BMP2 and STAT1 and mediates BMP2 upregulation and STAT1 downregulation, which promotes atherosclerotic calcification. Our results demonstrate the effect of ILF3 in atherosclerotic calcification. Inhibition of ILF3 may be a useful therapy for preventing and even reversing atherosclerotic calcification.

Copyright © 2021. Published by Elsevier Ltd.

J Mol Cell Cardiol: 30 Jul 2021; 161:39-52
Xie F, Cui QK, Wang ZY, Liu B, ... Wang Y, Zhang MX
J Mol Cell Cardiol: 30 Jul 2021; 161:39-52 | PMID: 34343541
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Abstract

IL4Rα signaling promotes neonatal cardiac regeneration and cardiomyocyte cell cycle activity.

Paddock SJ, Swift SK, Alencar-Almeida V, Kenarsary A, ... Patterson M, O\'Meara CC
Neonatal heart regeneration depends on proliferation of pre-existing cardiomyocytes, yet the mechanisms driving regeneration and cardiomyocyte proliferation are not comprehensively understood. We recently reported that the anti-inflammatory cytokine, interleukin 13 (IL13), promotes neonatal cardiac regeneration; however, the signaling pathway and cell types mediating this regenerative response remain unknown. Here, we hypothesized that expression of the type II heterodimer receptor for IL13, comprised of IL4Rα and IL13Rα1, expressed directly on cardiomyocytes mediates cardiomyocyte cell cycle and heart regeneration in neonatal mice. Our data demonstrate that indeed global deletion of one critical subunit of the type II receptor, IL4Rα (IL4Rα-/-), decreases cardiomyocyte proliferation during early postnatal development and significantly impairs cardiac regeneration following injury in neonatal mice. While multiple myocardial cell types express IL4Rα, we demonstrate that IL4Rα deletion specifically in cardiomyocytes mediates cell cycle activity and neonatal cardiac regeneration. This demonstrates for the first time a functional role for IL4Rα signaling directly on cardiomyocytes in vivo. Reciprocally, we examined the therapeutic benefit of activating the IL4Rα receptor in non-regenerative hearts via IL13 administration. Following myocardial infarction, administration of IL13 reduced scar size and promoted cardiomyocyte DNA synthesis and karyokinesis, but not complete cytokinesis, in 6-day old non-regenerative mice. Our data demonstrate a novel role for IL4Rα signaling directly on cardiomyocytes during heart regeneration and suggest the potential for type II receptor activation as one potential therapeutic target for promoting myocardial repair.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 30 Jul 2021; 161:62-74
Paddock SJ, Swift SK, Alencar-Almeida V, Kenarsary A, ... Patterson M, O'Meara CC
J Mol Cell Cardiol: 30 Jul 2021; 161:62-74 | PMID: 34343540
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Abstract

Engineering the aortic valve extracellular matrix through stages of development, aging, and disease.

Scott AJ, Simon LR, Hutson HN, Porras AM, Masters KS
For such a thin tissue, the aortic valve possesses an exquisitely complex, multi-layered extracellular matrix (ECM), and disruptions to this structure constitute one of the earliest hallmarks of fibrocalcific aortic valve disease (CAVD). The native valve structure provides a challenging target for engineers to mimic, but the development of advanced, ECM-based scaffolds may enable mechanistic and therapeutic discoveries that are not feasible in other culture or in vivo platforms. This review first discusses the ECM changes that occur during heart valve development, normal aging, onset of early-stage disease, and progression to late-stage disease. We then provide an overview of the bottom-up tissue engineering strategies that have been used to mimic the valvular ECM, and opportunities for advancement in these areas.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 29 Jul 2021; 161:1-8
Scott AJ, Simon LR, Hutson HN, Porras AM, Masters KS
J Mol Cell Cardiol: 29 Jul 2021; 161:1-8 | PMID: 34339757
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Abstract

Reperfusion mediates heme impairment with increased protein cysteine sulfonation of mitochondrial complex III in the post-ischemic heart.

Chen CL, Kang PT, Zhang L, Xiao K, ... Chilian WM, Chen YR
A serious consequence of myocardial ischemia-reperfusion injury (I/R) is oxidative damage, which causes mitochondrial dysfunction. The cascading ROS can propagate and potentially induce heme bleaching and protein cysteine sulfonation (PrSO3H) of the mitochondrial electron transport chain. Herein we studied the mechanism of I/R-mediated irreversible oxidative injury of complex III in mitochondria from rat hearts subjected to 30-min of ischemia and 24-h of reperfusion in vivo. In the I/R region, the catalytic activity of complex III was significantly impaired. Spectroscopic analysis indicated that I/R mediated the destruction of hemes b and c + c1 in the mitochondria, supporting I/R-mediated complex III impairment. However, no significant impairment of complex III activity and heme damage were observed in mitochondria from the risk region of rat hearts subjected only to 30-min ischemia, despite a decreased state 3 respiration. In the I/R mitochondria, carbamidomethylated C122/C125 of cytochrome c1 via alkylating complex III with a down regulation of HCCS was exclusively detected, supporting I/R-mediated thioether defect of heme c1. LC-MS/MS analysis showed that I/R mitochondria had intensely increased complex III PrSO3H levels at the C236 ligand of the [2Fe2S] cluster of the Rieske iron‑sulfur protein (uqcrfs1), thus impairing the electron transport activity. MS analysis also indicated increased PrSO3H of the hinge protein at C65 and of cytochrome c1 at C140 and C220, which are confined in the intermembrane space. MS analysis also showed that I/R extensively enhanced the PrSO3H of the core 1 (uqcrc1) and core 2 (uqcrc2) subunits in the matrix compartment, thus supporting the conclusion that complex III releases ROS to both sides of the inner membrane during reperfusion. Analysis of ischemic mitochondria indicated a modest reduction from the basal level of complex III PrSO3H detected in the mitochondria of sham control hearts, suggesting that the physiologic hyperoxygenation and ROS overproduction during reperfusion mediated the enhancement of complex III PrSO3H. In conclusion, reperfusion-mediated heme damage with increased PrSO3H controls oxidative injury to complex III and aggravates mitochondrial dysfunction in the post-ischemic heart.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 28 Jul 2021; 161:23-38
Chen CL, Kang PT, Zhang L, Xiao K, ... Chilian WM, Chen YR
J Mol Cell Cardiol: 28 Jul 2021; 161:23-38 | PMID: 34331972
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Abstract

Generation of microRNA-378a-deficient hiPSC as a novel tool to study its role in human cardiomyocytes.

Martyniak A, Andrysiak K, Motais B, Coste S, ... Stępniewski J, Dulak J
microRNA-378a (miR-378a) is one of the most highly expressed microRNAs in the heart. However, its role in the human cardiac tissue has not been fully understood. It was observed that miR-378a protects cardiomyocytes from hypertrophic growth by regulation of IGF1R and the expression of downstream kinases. Increased levels of miR-378a were reported in the serum of Duchenne muscular dystrophy (DMD) patients and female carriers of DMD gene-associated mutations with developed cardiomyopathy. In order to shed more light on the role of miR-378a in human cardiomyocytes and its potential involvement in DMD-related cardiomyopathy, we generated two human induced pluripotent stem cell (hiPSC) models; one with deletion of miR-378a and the second one with deletion of DMD exon 50 leading to the DMD phenotype. Our results indicate that lack of miR-378a does not influence the pluripotency of hiPSC and their ability to differentiate into cardiomyocytes (hiPSC-CM). miR-378a-deficient hiPSC-CM exhibited, however, significantly bigger size compared to the isogenic control cells, indicating the role of this miRNA in the hypertrophic growth of human cardiomyocytes. In accordance, the level of NFATc3, phosphoAKT, phosphoERK and ERK was higher in these cells compared to the control counterparts. A similar effect was achieved by silencing miR-378a with antagomirs. Of note, the percentage of cells with nuclear localization of NFATc3 was higher in miR-378a-deficient hiPSC-CM. Analysis of electrophysiological properties and Ca2+ oscillations revealed the decrease in the spike slope velocity and lower frequency of calcium spikes in miR-378a-deficient hiPSC-CM. Interestingly, the level of miR-378a increased gradually during cardiac differentiation of hiPSC. Of note, it was low until day 15 in differentiating DMD-deficient hiPSC-CM and then rose to a similar level as in the isogenic control counterparts. In summary, our findings confirmed the utility of hiPSC-based models for deciphering the role of miR-378a in the control and diseased human cardiomyocytes.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Mol Cell Cardiol: 27 Jul 2021; 160:128-141
Martyniak A, Andrysiak K, Motais B, Coste S, ... Stępniewski J, Dulak J
J Mol Cell Cardiol: 27 Jul 2021; 160:128-141 | PMID: 34329686
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This program is still in alpha version.