Computational model of cardiomyocyte apoptosis identifies mechanisms of tyrosine kinase inhibitor-induced cardiotoxicity
Despite clinical observations of cardiotoxicity among cancer patients treated with tyrosine kinase inhibitors (TKIs), the molecular mechanisms by which these drugs affect the heart remain largely unknown. Mechanistic understanding of TKI-induced cardiotoxicity has been limited in part due to the complexity of tyrosine kinase signaling pathways and the multi-targeted nature of many of these drugs. TKI treatment has been associated with reactive oxygen species generation, mitochondrial dysfunction, and apoptosis in cardiomyocytes. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - March 2, 2021 Category: Cytology Authors: Monika E. Grabowska, Bryan Chun, Raquel Moya, Jeffrey J. Saucerman Source Type: research

Cardiometabolic disease: Mechanisms to therapies
The world is witnessing the escalating spread of cardiometabolic diseases around the globe [1]. A longstanding challenge in high-income countries, this scourge now touches low-to-middle income countries. In 2005, 33% of the world's adult population (1.3  billion people) was overweight or obese. If the current trend continues, it is estimated that by 2030 nearly 60% of the world's adult population – more than 3 billion people – will be either overweight or obese [1]. Without question, these developments represent a global crisis that needs t o be urgently curbed. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - March 2, 2021 Category: Cytology Authors: Gabriele G. Schiattarella, Yibin Wang, Rong Tian, Joseph A. Hill Source Type: research

Txnip C247S mutation protects the heart against acute myocardial infarction
Thioredoxin-interacting protein (Txnip) is a novel molecular target with translational potential in diverse human diseases. Txnip has several established cellular actions including binding to thioredoxin, a scavenger of reactive oxygen species (ROS). It has been long recognized from in vitro evidence that Txnip forms a disulfide bridge through cysteine 247 (C247) with reduced thioredoxin to inhibit the anti-oxidative properties of thioredoxin. However, the physiological significance of the Txnip-thioredoxin interaction remains largely undefined in vivo. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 27, 2021 Category: Cytology Authors: Yoshinobu Nakayama, Nobuhiro Mukai, Bing F. Wang, Kristen Yang, Parth Patwari, Richard N. Kitsis, Jun Yoshioka Source Type: research

Computational models of cardiovascular regulatory mechanisms
Cardiovascular biology has a rich history of developing and using mathematical models dating to the first systems model of the cardiac action potential published in 1960 by Denis Noble in Nature. This early work set the stage for a rich array of mathematical and numerical models during the ensuing 60  years of cardiac and vascular biology at the molecular, cellular, tissue, organ and system scales. The next decade will see the first multi-scale computational models of cardiovascular physiology and biophysics that bridge all of these scales and predict system level phenotypes of specific pharma cological treatments, genet...
Source: Journal of Molecular and Cellular Cardiology - February 26, 2021 Category: Cytology Authors: Andrew McCulloch, Eleonora Grandi, Jeffrey Saucerman Source Type: research

Potential impacts of the cardiac troponin I mobile domain on myofilament activation and relaxation
This study uses a computational model to investigate the consequences of assuming that TnI regulates Tm movement via two actin-binding domains rather than one. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 26, 2021 Category: Cytology Authors: Jenette G. Creso, Stuart G. Campbell Source Type: research

Adaptation to exercise-induced stress is not dependent on cardiomyocyte α1A-adrenergic receptors
The ‘fight or flight’ response to physiological stress involves sympathetic nervous system activation, catecholamine release and adrenergic receptor stimulation. In the heart, this induces positive inotropy, previously attributed to the β1-adrenergic receptor subtype. However, the role of the α1A- adrenergic receptor, which has been suggested to be protective in cardiac pathology, has not been investigated in the setting of physiological stress. To explore this, we developed a tamoxifen-inducible, cardiomyocyte-specific α1A-adrenergic receptor knock-down mouse model, challenged mice to four wee...
Source: Journal of Molecular and Cellular Cardiology - February 26, 2021 Category: Cytology Authors: Xenia Kaidonis, Wenxing Niu, Andrea Y. Chan, Scott Kesteven, Jianxin Wu, Siiri E. Iismaa, Stephen Vatner, Michael Feneley, Robert M. Graham Source Type: research

Global identification of S-palmitoylated proteins and detection of palmitoylating (DHHC) enzymes in heart
High-throughput experiments suggest that almost 20% of human proteins may be S-palmitoylatable, a post-translational modification (PTM) whereby fatty acyl chains, most commonly palmitoyl chain, are linked to cysteine thiol groups that impact on protein trafficking, distribution and function. In human, protein S-palmitoylation is mediated by a group of 23 palmitoylating ‘Asp-His-His-Cys’ domain-containing (DHHC) enzymes. There is no information on the scope of protein S-palmitoylation, or the pattern of DHHC enzyme expression, in the heart. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 23, 2021 Category: Cytology Authors: Madeleine R. Miles, John Seo, Min Jiang, Zachary T. Wilson, Janay Little, Jon Hao, Joshua Andrade, Beatrix Ueberheide, Gea-Ny Tseng Source Type: research

Inhibiting microRNA-155 attenuates atrial fibrillation by targeting CACNA1C
Reduction in L-type Ca2+ current (ICa,L) density is a hallmark of the electrical remodeling in atrial fibrillation (AF). The expression of miR-155, whose predicted target gene is the α1c subunit of the calcium channel (CACNA1C), was upregulated in atrial cardiomyocytes (aCMs) from patients with paroxysmal AF.The study is to determine miR-155 could target the gene expression of ICa,L and contribute to electrical remodeling in AF. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 23, 2021 Category: Cytology Authors: Jiangang Wang, Qing Ye, Shuyun Bai, Pengfei Chen, Yichen Zhao, Xiaolong Ma, Chen Bai, Yang Liu, Meng Xin, Caiwu Zeng, Quan Liu, Cheng Zhao, Yan Yao, Yue Ma Source Type: research

The effect of variable troponin C mutation thin filament incorporation on cardiac muscle twitch contractions
One of the complexities of understanding the pathology of familial forms of cardiac diseases is the level of mutation incorporation in sarcomeres. Computational models of the sarcomere that are spatially explicit offer an approach to study aspects of mutational incorporation into myofilaments that are more challenging to get experimentally. We studied two well characterized mutations of cardiac TnC, L48Q and I61Q, that decrease or increase the release rate of Ca2+ from cTnC, k −Ca, resulting in HCM and DCM respectively [1]. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 23, 2021 Category: Cytology Authors: Srboljub M. Mijailovich, Momcilo Prodanovic, Corrado Poggesi, Joseph D. Powers, Jennifer Davis, Michael A. Geeves, Michael Regnier Source Type: research

Call for papers on topics of interest
JMCC is seeking submissions on the following topics of special interest in 2021 –22. Full-length original research, methods/how-to, short communication and letter to the editor will be considered. Manuscripts designated under these topics will be reviewed by a dedicated editorial task force with expedited schedule. The accepted manuscripts may be considered for presentation i n a ISHR-JMCC webinar and will be published with highlights under Hot-Topic series. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 22, 2021 Category: Cytology Source Type: research

Mapping genetic changes in the cAMP-signaling cascade in human atria
To obtain a quantitative expression profile of the main genes involved in the cAMP-signaling cascade in human control atria and in different cardiac pathologies. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 22, 2021 Category: Cytology Authors: Anne Garnier, Nadja I. Bork, Eric Jacquet, Svante Zipfel, Christian Mu ñoz-Guijosa, Istvan Baczkó, Hermann Reichenspurner, Patrick Donzeau-Gouge, Lars S. Maier, Dobromir Dobrev, Evaldas Girdauskas, Viacheslav O. Nikolaev, Rodolphe Fischmeister, Cristina Source Type: research

Lipoprotein compartmentalisation as a regulator of PCSK9 activity
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein whose function was only first eluded to in 2003 and has since found its way as a new treatment target within the clinic. It is one of the most striking examples of a rapid translation from a genetic-based discovery to an approved therapeutic. By studying families with familial hypercholesterolemia (FH), Boileau and colleagues uncovered a rare gain of function mutation in the PCSK9 gene. FH affects 1 in 250 individuals. Monogenic mutations in the low-density lipoprotein receptor (LDLR, common FH1) or in the apolipoprotein B gene (APOB, rare FH2) constituted ...
Source: Journal of Molecular and Cellular Cardiology - February 19, 2021 Category: Cytology Authors: Sean A. Burnap, Manuel Mayr Tags: Short communication Source Type: research

Evidence that the acetyltransferase Tip60 induces the DNA damage response and cell-cycle arrest in neonatal cardiomyocytes
Tip60, a pan-acetyltransferase encoded by the Kat5 gene, is enriched in the myocardium; however, its function in the heart is unknown. In cancer cells, Tip60 acetylates Atm (Ataxia-telangiectasia mutated), enabling its auto-phosphorylation (pAtm), which activates the DNA damage response (DDR). It was recently reported that activation of pAtm at the time of birth induces the DDR in cardiomyocytes (CMs), resulting in proliferative senescence. We therefore hypothesized that Tip60 initiates this process, and that depletion of Tip60 accordingly diminishes the DDR while extending the duration of CM cell-cycle activation. (Source...
Source: Journal of Molecular and Cellular Cardiology - February 17, 2021 Category: Cytology Authors: Xinrui Wang, Carri Lupton, Amelia Lauth, Tina C. Wan, Parker Foster, Michaela Patterson, John A. Auchampach, John W. Lough Source Type: research

Hypertrophic signaling compensates for contractile and metabolic consequences of DNA methyltransferase 3A loss in human cardiomyocytes
The role of DNA methylation in cardiomyocyte physiology and cardiac disease remains a matter of controversy. We have recently provided evidence for an important role of DNMT3A in human cardiomyocyte cell homeostasis and metabolism, using engineered heart tissue (EHT) generated from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes carrying a knockout of the de novo DNA methyltransferase DNMT3A. Unlike isogenic control EHT, knockout EHT displayed morphological abnormalities such as lipid accumulations inside cardiomyocytes associated with impaired mitochondrial metabolism, as well as functional defects and ...
Source: Journal of Molecular and Cellular Cardiology - February 11, 2021 Category: Cytology Authors: Alexandra Madsen, Julia Krause, Grit H öppner, Marc N. Hirt, Wilson Lek Wen Tan, Ives Lim, Arne Hansen, Viacheslav O. Nikolaev, Roger S.Y. Foo, Thomas Eschenhagen, Justus Stenzig Source Type: research

Periostin-expressing Schwann cells and endoneurial cardiac fibroblasts contribute to sympathetic nerve fasciculation after birth
The intracardiac nervous system (ICNS) is composed of neurons, in association with Schwann cells (SC) and endoneurial cardiac fibroblasts (ECF). Besides heart rhythm control, recent studies have implicated cardiac nerves in postnatal cardiac regeneration and cardiomyocyte size regulation, but cardiac SC and ECF remain understudied. During the postnatal period, the ICNS undergoes intense remodeling with nerve fasciculation and elongation throughout the myocardium, partially guided by the extracellular matrix (ECM). (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 11, 2021 Category: Cytology Authors: Luis Hortells, Evan C. Meyer, Zachary M. Thomas, Katherine E. Yutzey Source Type: research

Clinical epigenomics for cardiovascular disease: Diagnostics and therapies
The study of epigenomics has advanced in recent years to span the regulation of a single genetic locus to the structure and orientation of entire chromosomes within the nucleus. In this review, we focus on the challenges and opportunities of clinical epigenomics in cardiovascular disease. As an integrator of genetic and environmental inputs, and because of advances in measurement techniques that are highly reproducible and provide sequence information, the epigenome is a rich source of potential biosignatures of cardiovascular health and disease. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 6, 2021 Category: Cytology Authors: Matthew A. Fischer, Thomas M. Vondriska Source Type: research

Rad-GTPase contributes to heart rate via L-type calcium channel regulation
Sinoatrial node cardiomyocytes (SANcm) possess automatic, rhythmic electrical activity. SAN rate is influenced by autonomic nervous system input, including sympathetic nerve increases of heart rate (HR) via activation of β-adrenergic receptor signaling cascade (β-AR). L-type calcium channel (LTCC) activity contributes to membrane depolarization and is a central target of β-AR signaling. Recent studies revealed that the small G-protein Rad plays a central role in β-adrenergic receptor directed modulation of LTCC. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 5, 2021 Category: Cytology Authors: Bryana M. Levitan, Brooke M. Ahern, Ajoy Aloysius, Laura Brown, Yuan Wen, Douglas A. Andres, Jonathan Satin Source Type: research

β1-adrenergic receptor N-terminal cleavage by ADAM17; the mechanism for redox-dependent downregulation of cardiomyocyte β1-adrenergic receptors
β1-adrenergic receptors (β1ARs) are the principle mediators of catecholamine action in cardiomyocytes. We previously showed that the β1AR extracellular N-terminus is a target for post-translational modifications that impact on signaling responses. Specifically, we showed that the β1AR N-terminus carries O-glycan modifications at Ser37/Ser41, that O-glycosylation prevents β1AR N-terminal cleavage, and that N-terminal truncation influences β1AR signaling to downstream effectors. However, the site(s) and mechanism for β1AR N-terminal cleavage in cells was not identified. (Source: Journal of ...
Source: Journal of Molecular and Cellular Cardiology - February 5, 2021 Category: Cytology Authors: Jing Zhu, Susan F. Steinberg Source Type: research

Spen deficiency interferes with Connexin 43 expression and leads to heart failure in zebrafish
Genome-wide association studies identified Spen as a putative modifier of cardiac function, however, the precise function of Spen in the cardiovascular system is not known yet. Here, we analyzed for the first time the in vivo role of Spen in zebrafish and found that targeted Spen inactivation led to progressive impairment of cardiac function in the zebrafish embryo. In addition to diminished cardiac contractile force, Spen-deficient zebrafish embryos developed bradycardia, atrioventricular block and heart chamber fibrillation. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 4, 2021 Category: Cytology Authors: Manuel Rattka, S ören Westphal, Bernd M. Gahr, Steffen Just, Wolfgang Rottbauer Source Type: research

Computation-assisted targeted proteomics of alternative splicing protein isoforms in the human heart
Alternative splicing is prevalent in the heart and implicated in many cardiovascular diseases, but not every alternative transcript is translated and detecting non-canonical isoforms at the protein level remains challenging. Here we show the use of a computation-assisted targeted proteomics workflow to detect protein alternative isoforms in the human heart. We build on a recent strategy to integrate deep RNA-seq and large-scale mass spectrometry data to identify candidate translated isoform peptides. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 4, 2021 Category: Cytology Authors: Yu Han, Silas D. Wood, Julianna M. Wright, Vishantie Dostal, Edward Lau, Maggie P.Y. Lam Tags: Short communication Source Type: research

Phosphoproteomics of the developing heart identifies PERM1 - An outer mitochondrial membrane protein
Heart development relies on PTMs that control cardiomyocyte proliferation, differentiation and cardiac morphogenesis. We generated a map of phosphorylation sites during the early stages of cardiac postnatal development in mice; we quantified over 10,000 phosphorylation sites and 5000 proteins that were assigned to different pathways. Analysis of mitochondrial proteins led to the identification of PGC-1- and ERR-induced regulator in muscle 1 (PERM1), which is specifically expressed in skeletal muscle and heart tissue and associates with the outer mitochondrial membrane. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 4, 2021 Category: Cytology Authors: Sriram Aravamudhan, Clara T ürk, Theresa Bock, Lena Keufgens, Hendrik Nolte, Franziska Lang, Ramesh Kumar Krishnan, Tim König, Philipp Hammerschmidt, Natalie Schindler, Susanne Brodesser, Dieu Hien Rozsivalova, Elena Rugarli, Aleksandra Trifunovic, Jens Source Type: research

A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload
G protein-coupled receptor (GPCR) kinase 2 (GRK2) expression and activity are elevated early on in response to several forms of cardiovascular stress and are a hallmark of heart failure. Interestingly, though, in addition to its well-characterized role in regulating GPCRs, mounting evidence suggests a GRK2 “interactome” that underlies a great diversity in its functional roles. Several such GRK2 interacting partners are important for adaptive and maladaptive myocyte growth; therefore, an understanding of domain-specific interactions with signaling and regulatory molecules could lead to novel target s for heart f...
Source: Journal of Molecular and Cellular Cardiology - February 3, 2021 Category: Cytology Authors: Kamila M. Bledzka, Iyad H. Manaserh, Jessica Grondolsky, Jessica Pfleger, Rajika Roy, Erhe Gao, J. Kurt Chuprun, Walter J. Koch, Sarah M. Schumacher Source Type: research

Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload
We previously reported that upregulated AMP deaminase (AMPD) contributes to diastolic ventricular dysfunction via depletion of the adenine nucleotide pool in a rat model of type 2 diabetes (T2DM), Otsuka Long-Evans-Tokushima Fatty rats (OLETF). Meanwhile, AMPD promotes the formation of substrates of xanthine oxidoreductase (XOR), which produces ROS as a byproduct. Here, we tested the hypothesis that a functional link between upregulated AMPD and XOR is involved in ventricular dysfunction in T2DM rats. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 3, 2021 Category: Cytology Authors: Yusuke Igaki, Masaya Tannol, Tatsuya Sato, Hidemichi Kouzu, Toshifumi Ogawa, Arata Osanami, Toshiyuki Yano, Atsushi Kuno, Takayuki Miki, Takashi Nakamura, Tetsuji Miura Source Type: research

MicroRNA-21 regulates right ventricular remodeling secondary to pulmonary arterial pressure overload
Right ventricular (RV) function is a critical determinant of survival in patients with pulmonary arterial hypertension (PAH). While miR-21 is known to associate with vascular remodeling in small animal models of PAH, its role in RV remodeling in large animal models has not been characterized. Herein, we investigated the role of miR-21 in RV dysfunction using a sheep model of PAH secondary to pulmonary arterial constriction (PAC). RV structural and functional remodeling were examined using ultrasound imaging. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 3, 2021 Category: Cytology Authors: Wei-Ting Chang, Sudeshna Fisch, Seema Dangwal, Jahan Mohebali, Amy G. Fiedler, Michael Chen, Chih-Hsin Hsu, Yanfei Yang, Yiling Qiu, Kevin M. Alexander, Frederick Y. Chen, Ronglih Liao Source Type: research

Computational modeling approaches to cAMP/PKA signaling in cardiomyocytes
The cAMP/PKA pathway is a fundamental regulator of excitation-contraction coupling in cardiomyocytes. Activation of cAMP has a variety of downstream effects on cardiac function including enhanced contraction, accelerated relaxation, adaptive stress response, mitochondrial regulation, and gene transcription. Experimental advances have shed light on the compartmentation of cAMP and PKA, which allow for control over the varied targets of these second messengers and is disrupted in heart failure conditions. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - February 3, 2021 Category: Cytology Authors: Kimberly J. McCabe, Padmini Rangamani Source Type: research

Spatial N-glycomics of the human aortic valve in development and pediatric endstage congenital aortic valve stenosis
Congenital aortic valve stenosis (AS) progresses as an obstructive narrowing of the aortic orifice due to deregulated extracellular matrix (ECM) production by aortic valve (AV) leaflets and leads to heart failure with no effective therapies. Changes in glycoprotein and proteoglycan distribution are a hallmark of AS, yet valvular carbohydrate content remains virtually uncharacterized at the molecular level. While almost all glycoproteins clinically linked to stenotic valvular modeling contain multiple sites for N-glycosylation, there are very few reports aimed at understanding how N-glycosylation contributes to the valve st...
Source: Journal of Molecular and Cellular Cardiology - January 28, 2021 Category: Cytology Authors: Peggi M. Angel, Richard R. Drake, Yeonhee Park, Cassandra L. Clift, Connor West, Savanna Berkhiser, Gary Hardiman, Anand S. Mehta, David Bichell, Yan Ru Su Source Type: research

Aging in reverse: Reactivating developmental signaling for cardiomyocyte proliferation
Mammalian heart is considered postmitotic with limited cardiomyocyte (CM) turnover during lifetime of an individual [1]. Adult CMs are typically unable to complete the cell cycle and respond to growth signals by hypertrophy or incomplete cytokinesis resulting in binucleation and/or polyploidization, considered to be major hurdles in CM proliferation and regeneration [2]. Ensuing years have seen a tremendous effort to delineate CM cell cycle and develop strategies that promote cell cycle reentry and CM mediated regeneration of the heart following injury. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - January 15, 2021 Category: Cytology Authors: Vagner Oliveira Carvalho Rigaud, Mohsin Khan Tags: Short communication Source Type: research

Diverging consequences of hexosamine biosynthesis in cardiovascular disease
In the stressed heart, metabolic remodeling precedes most, if not all, other pathophysiological changes [1]. When the heart is not stressed, it relies on fat for energy provision, with glucose being an additional energy source, while lactate, ketone bodies, and amino acids contribute as well, but do so only to a small extent. As a metabolic omnivore, the heart switches its nutrient preference towards more glucose under stress. After uptake, glucose is converted to pyruvate in the glycolytic pathway (Fig. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 30, 2020 Category: Cytology Authors: Qinfeng Li, Heinrich Taegtmeyer, Zhao V. Wang Tags: Letter to the editor Source Type: research

Diverse consequences of hexosamine biosynthesis in cardiovascular disease
In the stressed heart, metabolic remodeling precedes most, if not all, other pathophysiological changes [1]. When the heart is not stressed, it relies on fat for energy provision, with glucose being an additional energy source, while lactate, ketone bodies, and amino acids contribute as well, but do so only to a small extent. As a metabolic omnivore, the heart switches its nutrient preference towards more glucose under stress. After uptake, glucose is converted to pyruvate in the glycolytic pathway (Fig. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 30, 2020 Category: Cytology Authors: Qinfeng Li, Heinrich Taegtmeyer, Zhao V. Wang Tags: Letter to the editor Source Type: research

Blockade of sodium ‑calcium exchanger via ORM-10962 attenuates cardiac alternans
Repolarization alternans, a periodic oscillation of long-short action potential duration, is an important source of arrhythmogenic substrate, although the mechanisms driving it are insufficiently understood. Despite its relevance as an arrhythmia precursor, there are no successful therapies able to target it specifically. We hypothesized that blockade of the sodium ‑calcium exchanger (NCX) could inhibit alternans. The effects of the selective NCX blocker ORM-10962 were evaluated on action potentials measured with microelectrodes from canine papillary muscle preparations, and calcium transients measured using Fluo4-AM fro...
Source: Journal of Molecular and Cellular Cardiology - December 28, 2020 Category: Cytology Authors: Jozefina Szlov ák, Jakub Tomek, Xin Zhou, Noémi Tóth, Roland Veress, Balázs Horváth, Norbert Szentandrássy, Jouko Levijoki, Julius Gy. Papp, Neil Herring, András Varró, David A. Eisner, Blanca Rodriguez, Norbert Nagy Source Type: research

Soluble epoxide hydrolase deficiency attenuates lipotoxic cardiomyopathy via upregulation of AMPK-mTORC mediated autophagy
Obesity-driven cardiac lipid accumulation can progress to lipotoxic cardiomyopathy. Soluble epoxide hydrolase (sEH) is the major enzyme that metabolizes epoxyeicosatrienoic acids (EETs), which have biological activity of regulating lipid metabolism. The current study explores the unknown role of sEH deficiency in lipotoxic cardiomyopathy and its underlying mechanism. Wild-type and Ephx2 knock out (sEH KO) C57BL/6  J mice were fed with high-fat diet (HFD) for 24 weeks to induce lipotoxic cardiomyopathy animal models. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 27, 2020 Category: Cytology Authors: Luyun Wang, Daqiang Zhao, Liangqiu Tang, Huihui Li, Zhaoyu Liu, Jingwei Gao, Matthew L. Edin, Huanji Zhang, Kun Zhang, Jie Chen, Xinhong Zhu, Daowen Wang, Darryl C. Zeldin, Bruce D. Hammock, Jingfeng Wang, Hui Huang Source Type: research

Disrupted branched-chain amino acid catabolism impair cardiac insulin signaling and is associated with adverse cardiometabolic outcomes
Branched-chain amino acids (BCAAs), leucine (Leu), isoleucine (Ile) and valine (Val), account for ~20% of dietary protein intake [1]. BCAAs are reversibly transaminated to their corresponding branched-chain keto acids (BCKAs) by branched-chain aminotransferase (BCAT). BCKAs are oxidatively decarboxylated by branched-chain ketoacid dehydrogenase (BCKDH). BCKDH activity is inhibited by branched-chain ketoacid dehydrogenase kinase (BCKDK) mediated inhibitory phosphorylation or activated by protein phosphatase 2C (PP2Cm) induced dephosphorylation [1]. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 27, 2020 Category: Cytology Authors: Dipsikha Biswas, Thomas Pulinilkunnil Tags: Letter to the editor Source Type: research

Soluble epoxide hydrolase deficiency attenuates lipotoxic cardiomyopathy via upregulation of AMPK-mTORC mediated autophagy
Obesity-driven cardiac lipid accumulation can progress to lipotoxic cardiomyopathy. Soluble epoxide hydrolase (sEH) is the major enzyme that metabolizes epoxyeicosatrienoic acids (EETs), which have biological activity of regulating lipid metabolism. The current study explores the unknown role of sEH deficiency in lipotoxic cardiomyopathy and its underlying mechanism. Wild-type and Ephx2 knock out (sEH KO) C57BL/6  J mice were fed with high-fat diet (HFD) for 24 weeks to induce lipotoxic cardiomyopathy animal models. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 27, 2020 Category: Cytology Authors: Luyun Wang, Daqiang Zhao, Liangqiu Tang, Huihui Li, Zhaoyu Liu, Jingwei Gao, Matthew L. Edin, Huanji Zhang, Kun Zhang, Jie Chen, Xinhong Zhu, Daowen Wang, Darryl C. Zeldin, Bruce D. Hammock, Jingfeng Wang, Hui Huang Source Type: research

Adverse effects of hydroxychloroquine and azithromycin on contractility and arrhythmogenicity revealed by human engineered cardiac tissues
The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic as declared by World Health Organization (WHO). In the absence of an effective treatment in early 2020, different drugs with unknown effectiveness, including antimalarial hydroxychloroquine (HCQ), with or without concurrent administration with azithromycin (AZM), have been tested for treating COVID-19 patients with developed pneumonia. However, the efficacy and safety of HCQ and/or AZM have been questioned by recent clinical reports. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 26, 2020 Category: Cytology Authors: Andy On-Tik Wong, Bimal Gurung, Wing Sum Wong, Suet Yee Mak, Wan Wai Tse, Chloe M. Li, Deborah K. Lieu, Kevin D. Costa, Ronald A. Li, Roger J. Hajjar Tags: Short communication Source Type: research

Mechanisms underlying age-associated manifestation of cardiac sodium channel gain-of-function
Cardiac action potentials are initiated by sodium ion (Na+) influx through voltage-gated Na+ channels. Na+ channel gain-of-function (GOF) can arise in inherited conditions due to mutations in the gene encoding the cardiac Na+ channel, such as Long QT syndrome type 3 (LQT3). LQT3 can be a “concealed” disease, as patients with LQT3-associated mutations can remain asymptomatic until later in life; however, arrhythmias can also arise early in life in LQT3 patients, demonstrating a complex age-associated manifestation. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 26, 2020 Category: Cytology Authors: Madison B. Nowak, Steven Poelzing, Seth H. Weinberg Source Type: research

Pathophysiology and pharmacological management of pulmonary and cardiovascular features of COVID-19
The first confirmed case of novel Coronavirus Disease 2019 (COVID-19) in the United States was reported on January 20, 2020. As of November 24, 2020, close to 12.2 million cases of COVID-19 was confirmed in the US, with over 255,958 deaths. The rapid transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), its unusual and divergent presentation has strengthened the status of COVID-19 as a major public health threat. In this review, we aim to 1- discuss the epidemiological data from various COVID-19 patient cohorts around the world and the USA as well the associated risk factors; 2- summarize the pathop...
Source: Journal of Molecular and Cellular Cardiology - December 26, 2020 Category: Cytology Authors: Walid Hamouche, Malik Bisserier, Agnieszka Brojakowska, Abrisham Eskandari, Kenneth Fish, David A. Goukassian, Lahouaria Hadri Source Type: research

NADPH oxidase promotes PCSK9 secretion in macrophages
Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a serine protease that binds to the low-density lipoprotein receptor (LDLr), leading to the degradation of the LDLr and subsequently to higher level of low-density lipoprotein (LDL) [1]. PCSK9 is predominantly produced in the liver, kidney and small intestine [2]. An increasing body of evidence demonstrates that PCSK9 is also highly expressed in vascular cells (e.g. endothelial cells and smooth muscle cells) and macrophages, particularly in the condition with pro-inflammatory stimuli [3]. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 25, 2020 Category: Cytology Authors: Xiao Li, Anna N. Brickell, Xianwei Wang, Sichang Zhou, Zufeng Ding Tags: Letter to the editor Source Type: research

Elevated EZH2 in ischemic heart disease epigenetically mediates suppression of NaV1.5 expression
Suppression of the cardiac sodium channel NaV1.5 leads to fatal arrhythmias in ischemic heart disease (IHD). However, the transcriptional regulation of NaV1.5 in cardiac ischemia is still unclear. Our studies are aimed to investigate the expression of enhancer of zeste homolog 2 (EZH2) in IHD and regulation of cardiac NaV1.5 expression by EZH2. Human heart tissue was obtained from IHD and non-failing heart (NFH) patients; mouse heart tissue was obtained from the peri-infarct zone of hearts with myocardial infarction (MI) and hearts with a sham procedure. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 25, 2020 Category: Cytology Authors: Limei Zhao, Tao You, Yan Lu, Shin Lin, Faqian Li, Haodong Xu Source Type: research

Suppression of canonical TGF- β signaling enables GATA4 to interact with H3K27me3 demethylase JMJD3 to promote cardiomyogenesis
Direct reprogramming of fibroblasts into cardiomyocytes (CMs) represents a promising strategy to regenerate CMs lost after ischemic heart injury. Overexpression of GATA4, HAND2, MEF2C, TBX5, miR-1, and miR-133 (GHMT2m) along with transforming growth factor beta (TGF- β) inhibition efficiently promotes reprogramming. However, the mechanisms by which TGF-β blockade promotes cardiac reprogramming remain unknown. Here, we identify interactions between the histone H3 lysine 27 trimethylation (H3K27me3) – demethylase JMJD3, the SWI/SNF remodeling complex subunit B RG1, and cardiac transcription factors. (Source: ...
Source: Journal of Molecular and Cellular Cardiology - December 24, 2020 Category: Cytology Authors: Andrew S. Riching, Etienne Danis, Yuanbiao Zhao, Yingqiong Cao, Congwu Chi, Rushita A. Bagchi, Brianna J. Klein, Hongyan Xu, Tatiana G. Kutateladze, Timothy A. McKinsey, Peter M. Buttrick, Kunhua Song Source Type: research

Nano-scale morphology of cardiomyocyte t-tubule/sarcoplasmic reticulum junctions revealed by ultra-rapid high-pressure freezing and electron tomography
Detailed knowledge of the ultrastructure of intracellular compartments is a prerequisite for our understanding of how cells function. In cardiac muscle cells, close apposition of transverse (t)-tubule (TT) and sarcoplasmic reticulum (SR) membranes supports stable high-gain excitation-contraction coupling. Here, the fine structure of this key intracellular element is examined in rabbit and mouse ventricular cardiomyocytes, using ultra-rapid high-pressure freezing (HPF, omitting aldehyde fixation) and electron microscopy. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 20, 2020 Category: Cytology Authors: E.A. Rog-Zielinska, R. Moss, W. Kaltenbacher, J. Greiner, P. Verkade, G. Seemann, P. Kohl, M.B. Cannell Source Type: research

Considerations for using isolated cell systems to understand cardiac metabolism and biology
Changes in myocardial metabolic activity are fundamentally linked to cardiac health and remodeling. Primary cardiomyocytes, induced pluripotent stem cell-derived cardiomyocytes, and transformed cardiomyocyte cell lines are common models used to understand how (patho)physiological conditions or stimuli contribute to changes in cardiac metabolism. These cell models are helpful also for defining metabolic mechanisms of cardiac dysfunction and remodeling. Although technical advances have improved our capacity to measure cardiomyocyte metabolism, there is often heterogeneity in metabolic assay protocols and cell models, which c...
Source: Journal of Molecular and Cellular Cardiology - December 20, 2020 Category: Cytology Authors: Lindsey A. McNally, Tariq Altamimi, Kyle Fulghum, Bradford G. Hill Tags: Review article Source Type: research

The role of β-adrenergic system remodeling in human heart failure: A mechanistic investigation
β-adrenergic receptor antagonists (β-blockers) are extensively used to improve cardiac performance in heart failure (HF), but the electrical improvements with these clinical treatments are not fully understood. The aim of this study was to analyze the electrophysiological effects of β-adrenergic system remodeling in heart failure with reduced ejection fraction and the underlying mechanisms. We used a combined mathematical model that integrated β-adrenergic signaling with electrophysiology and calcium cycling in human ventricular myocytes. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 14, 2020 Category: Cytology Authors: Maria T. Mora, Jingqi Q.X. Gong, Eric A. Sobie, Beatriz Trenor Source Type: research

SupErbB monocytes? Innate immune cells help the heart adapt
Acute immune cell recruitment and activation occurs in response to virtually every tissue stress or injury. In the heart, ischemia is the prototypical paradigm in which myeloid cells such as monocytes, macrophages or neutrophils modulate acute wound healing or prolonged inflammation and scarring. However, a growing body of literature has demonstrated diverse roles for myeloid cells in non-ischemic cardiomyopathies, in metabolic syndromes, and in maintenance of cardiac homeostasis. Moreover, the intricacies of myeloid cells have expanded and considerable phenotypic diversity even among a single cell type is now well recogni...
Source: Journal of Molecular and Cellular Cardiology - December 10, 2020 Category: Cytology Authors: Ronald J. Vagnozzi Tags: Editorial Source Type: research

Ubiquitin-like protein FAT10 suppresses SIRT1-mediated autophagy to protect against ischemic myocardial injury
Autophagy plays a deleterious role in ischemic myocardial injury. The deacetylase SIRT1 is a well-established regulator of autophagy that can be modified by the ubiquitin-like protein SUMO1. Our previous work demonstrated that another ubiquitin-like protein, FAT10, exerts cardioprotective effects against myocardial ischemia by stabilizing the caveolin-3 protein; however, the effects of FAT10 on autophagy through SIRT1 are unclear. Here, we constructed a Fat10-knockout rat model to evaluate the role of FAT10 in autophagy. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 8, 2020 Category: Cytology Authors: Rong Wan, Ping Yuan, Linjuan Guo, Jianghua Shao, Xiao Liu, Wei Lai, Qiling Kong, Leifeng Chen, Jin Ge, Zhenyan Xu, Jinyan Xie, Yang Shen, Jianping Hu, Qiongqiong Zhou, Jianhua Yu, Zhenhong Jiang, Xinghua Jiang, Kui Hong Source Type: research

Gut microbiome - A potential mediator of pathogenesis in heart failure and its comorbidities: State-of-the-art review
Gut microbiome (GMB) has been increasingly recognized as a contributor to development and progression of heart failure (HF), immune-mediated subtypes of cardiomyopathy (myocarditis and anthracycline-induced cardiotoxicity), response to certain cardiovascular drugs, and HF-related comorbidities, such as chronic kidney disease, cardiorenal syndrome, insulin resistance, malnutrition, and cardiac cachexia. Gut microbiome is also responsible for the “gut hypothesis” of HF, which explains the adverse effects of gut barrier dysfunction and translocation of GMB on the progression of HF. (Source: Journal of Molecular an...
Source: Journal of Molecular and Cellular Cardiology - December 8, 2020 Category: Cytology Authors: Petra Mamic, Thanat Chaikijurajai, W.H. Wilson Tang Source Type: research

Downregulation of the zinc transporter SLC39A13 (ZIP13) is responsible for the activation of CaMKII at reperfusion and leads to myocardial ischemia/reperfusion injury in mouse hearts
This study reports that ZIP13 (SLC39A13), a zinc transporter, plays a role in myocardial I/R injury by modulating the Ca2+ signaling pathway rather than by regulating Zn2+ transport. ZIP13 is downregulated upon reperfusion in mouse hearts or in H9c2 cells at reoxygenation. Ca2+ but not Zn2+ was responsible for ZIP13 downregulation, implying that ZIP13 may play a role in I/R injury through the Ca2+ signaling pathway. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 8, 2020 Category: Cytology Authors: Jie Wang, Xinxin Cheng, Huanhuan Zhao, Qing Yang, Zhelong Xu Source Type: research

Corrigendum to “Sustained activation of ADP/P2ry12 signaling induces SMC senescence contributing to thoracic aortic aneurysm/dissection” [Journal of molecular and cellular cardiology 99 (2016): 76–86.]
The authors regret that during the preparation of high-resolution figures for this manuscript's publication, we cropped the original image to fit the whole figure. The image in Fig. 1F (0 uM) was inadvertently replaced with image from Fig. 1G (6  h). The published version of Fig. 1 is therefore incorrect. The corrected version of Fig. 1F& G is shown below. Also, the original images were shown with a red box indicated where the portion of the presentative images was cropped. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 7, 2020 Category: Cytology Authors: Wen-Mei Zhang, Yan Liu, Tao-Tao Li, Chun-Mei Piao, Ou Liu, Jun-Ling Liu, Yong-Fen Qi, Li-Xin Jia, Jie Du Tags: Corrigendum Source Type: research

Mitochondrial Ca2+, redox environment and ROS emission in heart failure: Two sides of the same coin?
Heart failure (HF) is a progressive, debilitating condition characterized, in part, by altered ionic equilibria, increased ROS production and impaired cellular energy metabolism, contributing to variable profiles of systolic and diastolic dysfunction with significant functional limitations and risk of premature death. We summarize current knowledge concerning changes of intracellular Na+ and Ca2+ control mechanisms during the disease progression and their consequences on mitochondrial Ca2+ homeostasis and the shift in redox balance. (Source: Journal of Molecular and Cellular Cardiology)
Source: Journal of Molecular and Cellular Cardiology - December 7, 2020 Category: Cytology Authors: Sonia Cortassa, Magdalena Juhaszova, Miguel A. Aon, Dmitry B. Zorov, Steven J. Sollott Source Type: research