SR Ca 2+ -leak and disordered excitation-contraction coupling as the basis for arrhythmogenic and negative inotropic effects of acute ethanol exposure

Mustroph, Julian; Wagemann, Olivia; Lebek, Simon; Tarnowski, Daniel; Ackermann, Jasmin; Drzymalski, Marzena; Pabel, Steffen; Schmid, Çhristof; Wagner, Stefan; Sossalla, Samuel; Maier, Lars S.; Neef, Stefan

doi:10.1016/j.yjmcc.2018.02.002

Cited by 28 publications

(47 citation statements)

References 53 publications

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“…Alteration in the expression of ion channel-related proteins represents another category of the differentially expressed proteins in hiPSC-CMs treated with EtOH. This finding is consistent with the observation that treatment of hiPSC-CMs with EtOH triggered Ca 2+ transient abnormality as well as the growing evidence that EtOH exposure increases the risk of arrhythmias and negative inotropic effects via Ca 2+ handling defects and disordered excitation-contraction coupling (Mustroph et al, 2018(Mustroph et al, , 2019Voskoboinik et al, 2016). Since the ion transporting requires the assistance of Fig.…”

Section: Discussionsupporting

confidence: 91%

Proteomic Profiling Reveals Roles of Stress Response, Ca²⁺ Transient Dysregulation, and Novel Signaling Pathways in Alcohol‐Induced Cardiotoxicity

Sun

Forghani

et al. 2020

Alcoholism Clin & Exp Res

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Background: Alcohol use in pregnancy increases the risk of abnormal cardiac development, and excessive alcohol consumption in adults can induce cardiomyopathy, contractile dysfunction, and arrhythmias. Understanding molecular mechanisms underlying alcohol-induced cardiac toxicity could provide guidance in the development of therapeutic strategies. Methods: We have performed proteomic and bioinformatic analysis to examine protein alterations globally and quantitatively in cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) treated with ethanol (EtOH). Proteins in both cell lysates and extracellular culture media were systematically quantitated. Results: Treatment with EtOH caused severe detrimental effects on hiPSC-CMs as indicated by significant cell death and deranged Ca 2+ handling. Treatment of hiPSC-CMs with EtOH significantly affected proteins responsible for stress response (e.g., GPX1 and HSPs), ion channel-related proteins (e.g. ATP1A2), myofibril structure proteins (e.g., MYL2/3), and those involved in focal adhesion and extracellular matrix (e.g., ILK and PXN). Proteins involved in the TNF receptor-associated factor 2 signaling (e.g., CPNE1 and TNIK) were also affected by EtOH treatment. Conclusions: The observed changes in protein expression highlight the involvement of oxidative stress and dysregulation of Ca 2+ handling and contraction while also implicating potential novel targets in alcohol-induced cardiotoxicity. These findings facilitate further exploration of potential mechanisms, discovery of novel biomarkers, and development of targeted therapeutics against EtOH-induced cardiotoxicity.

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Section: Discussionsupporting

confidence: 91%

Proteomic Profiling Reveals Roles of Stress Response, Ca²⁺ Transient Dysregulation, and Novel Signaling Pathways in Alcohol‐Induced Cardiotoxicity

Sun

Forghani

et al. 2020

Alcoholism Clin & Exp Res

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“…Sample sizes (n) are denoted in the center of the graphs for the control and treatment groups. ventricular CMs (Mustroph et al, 2018). Similarly, we observed persistent irregular Ca 2þ transients indicated by oscillations of diastolic cytosolic Ca 2þ (Ca 2þ waves) in hiPSC-CMs.…”

Section: Discussionsupporting

confidence: 67%

Cardiac Toxicity From Ethanol Exposure in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Rampoldi

Singh

et al. 2019

Toxicological Sciences

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Alcohol use prior to and during pregnancy remains a significant societal problem and can lead to developmental fetal abnormalities including compromised myocardia function and increased risk for heart disease later in life. Alcohol-induced cardiac toxicity has traditionally been studied in animal-based models. These models have limitations due to physiological differences from human cardiomyocytes (CMs) and are also not suitable for high-throughput screening. We hypothesized that human-induced pluripotent stem cell-derived CMs (hiPSC-CMs) could serve as a useful tool to study alcohol-induced cardiac defects and/or toxicity. In this study, hiPSC-CMs were treated with ethanol at doses corresponding to the clinically relevant levels of alcohol intoxication. hiPSC-CMs exposed to ethanol showed a dose-dependent increase in cellular damage and decrease in cell viability, corresponding to increased production of reactive oxygen species. Furthermore, ethanol exposure also generated dose-dependent increased irregular Ca 2þ transients and contractility in hiPSC-CMs. RNA-seq analysis showed significant alteration in genes belonging to the potassium voltage-gated channel family or solute carrier family, partially explaining the irregular Ca 2þ transients and contractility in ethanol-treated hiPSC-CMs. RNA-seq also showed significant upregulation in the expression of genes associated with collagen and extracellular matrix modeling, and downregulation of genes involved in cardiovascular system development and actin filament-based process. These results suggest that hiPSC-CMs can be a novel and physiologically relevant system for the study of alcohol-induced cardiac toxicity.

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“…Ethanol reduces I Na , I Ca,L , I to , I Kur , and I Kr [8,11,12] and exhibits dual effects on I K1 and I K,ACh [9,10], with inhibition of these latter currents at low concentrations and augmentation at high concentrations. Moreover, ethanol also enhanced I NCX , sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) function and SR Ca 2+ leak, increasing proarrhythmic spontaneous Ca 2+ release events [13]. These experimental findings were reproduced in human right atrial (RA) [16] and left ventricular (LV) [17] cardiomyocyte models ( Fig.…”

Section: Acute Concentration-dependent Effects Of Ethanol On Cardiomymentioning

confidence: 67%

“…Bottom panels: peak currents of different ion channels relative to the baseline condition (not shown) with 0 mM ethanol. Experimental data are shown in white bars ([*] = [8], [#] = [9], [%] = [11], [^] = [12], [@] = [10], [&] = [13]), and simulated counterparts in blue bars. For I K1 and I K,ACh the relative change is shown for both the inward current (at −120 mV and − 110 mV) and the outward current at (−40 mV and − 50 mV) through these channels.…”

Section: Acute Concentration-dependent Effects Of Ethanol On Cardiomymentioning

confidence: 99%

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

Sutanto

Cluitmans

Dobrev

et al. 2020

Journal of Molecular and Cellular Cardiology

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Acute excessive ethyl alcohol (ethanol) consumption alters cardiac electrophysiology and can evoke cardiac arrhythmias, e.g., in 'holiday heart syndrome'. Ethanol acutely modulates numerous targets in cardiomyocytes, including ion channels, Ca 2+-handling proteins and gap junctions. However, the mechanisms underlying ethanol-induced arrhythmogenesis remain incompletely understood and difficult to study experimentally due to the multiple electrophysiological targets involved and their potential interactions with preexisting electrophysiological or structural substrates. Here, we employed cellular-and tissue-level in-silico analyses to characterize the acute effects of ethanol on cardiac electrophysiology and arrhythmogenesis. Acute electrophysiological effects of ethanol were incorporated into human atrial and ventricular cardiomyocyte computer models: reduced I Na , I Ca,L , I to , I Kr and I Kur , dual effects on I K1 and I K,ACh (inhibition at low and augmentation at high concentrations), and increased I NCX and SR Ca 2+ leak. Multiscale simulations in the absence or presence of preexistent atrial fibrillation or heart-failure-related remodeling demonstrated that low ethanol concentrations prolonged atrial action-potential duration (APD) without effects on ventricular APD. Conversely, high ethanol concentrations abbreviated atrial APD and prolonged ventricular APD. High ethanol concentrations promoted reentry in tissue simulations, but the extent of reentry promotion was dependent on the presence of altered intercellular coupling, and the degree, type, and pattern of fibrosis. Taken together, these data provide novel mechanistic insight into the potential proarrhythmic interactions between a preexisting substrate and acute changes in cardiac electrophysiology. In particular, acute ethanol exposure has concentration-dependent electrophysiological effects that differ between atria and ventricles, and between healthy and diseased hearts. Low concentrations of ethanol can have anti-fibrillatory effects in atria, whereas high concentrations promote the inducibility and maintenance of reentrant atrial and ventricular arrhythmias, supporting a role for limiting alcohol intake as part of cardiac arrhythmia management.

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SR Ca 2+ -leak and disordered excitation-contraction coupling as the basis for arrhythmogenic and negative inotropic effects of acute ethanol exposure

Cited by 28 publications

References 53 publications

Proteomic Profiling Reveals Roles of Stress Response, Ca²⁺ Transient Dysregulation, and Novel Signaling Pathways in Alcohol‐Induced Cardiotoxicity

Proteomic Profiling Reveals Roles of Stress Response, Ca²⁺ Transient Dysregulation, and Novel Signaling Pathways in Alcohol‐Induced Cardiotoxicity

Cardiac Toxicity From Ethanol Exposure in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

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SR Ca 2+ -leak and disordered excitation-contraction coupling as the basis for arrhythmogenic and negative inotropic effects of acute ethanol exposure

Cited by 28 publications

References 53 publications

Proteomic Profiling Reveals Roles of Stress Response, Ca2+ Transient Dysregulation, and Novel Signaling Pathways in Alcohol‐Induced Cardiotoxicity

Proteomic Profiling Reveals Roles of Stress Response, Ca2+ Transient Dysregulation, and Novel Signaling Pathways in Alcohol‐Induced Cardiotoxicity

Cardiac Toxicity From Ethanol Exposure in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Acute effects of alcohol on cardiac electrophysiology and arrhythmogenesis: Insights from multiscale in silico analyses

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Proteomic Profiling Reveals Roles of Stress Response, Ca²⁺ Transient Dysregulation, and Novel Signaling Pathways in Alcohol‐Induced Cardiotoxicity

Proteomic Profiling Reveals Roles of Stress Response, Ca²⁺ Transient Dysregulation, and Novel Signaling Pathways in Alcohol‐Induced Cardiotoxicity