Pub Date : 2025-12-05DOI: 10.1016/j.yjmcc.2025.12.003
Yongjun Wang , Shane R. Zhao , Dong Han , Wenshu Zeng , Mohamed Rafiuddin Ahmed , Xulei Qin , Qiang Liu , Joe Z. Zhang , Jayakumar Rajadas , Joseph C. Wu
{"title":"Galangin alleviates cardiac ischemia/reperfusion injury in human iPSC-derived cardiomyocytes and animal models","authors":"Yongjun Wang , Shane R. Zhao , Dong Han , Wenshu Zeng , Mohamed Rafiuddin Ahmed , Xulei Qin , Qiang Liu , Joe Z. Zhang , Jayakumar Rajadas , Joseph C. Wu","doi":"10.1016/j.yjmcc.2025.12.003","DOIUrl":"10.1016/j.yjmcc.2025.12.003","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 94-97"},"PeriodicalIF":4.7,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.yjmcc.2025.12.001
Alexandre Lewalle , Gregory Milburn , Jania Bell , Kenneth S. Campbell , Steven A. Niederer
In humans, the left atria (LA) and the left ventricle (LV) play distinct physiological roles and express sarcomeric proteins with chamber-specific patterns. Despite these important differences, most multi-chamber descriptions of the heart assume uniform myocardial properties. To facilitate a more accurate representation of cardiac function, we measured and compared the contractile properties of isolated skinned human LA and LV muscle fibers at 37 . Our experimental measurements included the length-dependent activation (LDA) of force in the isometric steady state, the force response to small quick length changes, and tension redevelopment dynamics. The LV measurements display more pronounced LDA behavior compared to LA, whereas the LA dynamics is generally faster than LV.
To elucidate these differences mechanistically, we used the LA and LV experimental datasets to fit a biophysical model framework to produce a representative model for each chamber. Our Bayesian statistical approach aimed to maximize the objectivity of the model calibrations and to allow a systematic assessment of chamber-specific parameter differences. Passive mechanical properties emerge as the principal determinant of LDA behavior. However, variations in cross-bridge cycling kinetics account more significantly for LA/LV differences in the ATP consumption to produce a given isometric force.
These results constitute the first systematic biophysical comparison of LA and LV cardiomyocyte contraction mechanics in humans, paving the way to further investigation of their roles within the broader cardiovascular physiological context.
{"title":"Human atrial skinned muscle fibers exhibit reduced length-dependent activation but show faster force development kinetics than ventricular muscle","authors":"Alexandre Lewalle , Gregory Milburn , Jania Bell , Kenneth S. Campbell , Steven A. Niederer","doi":"10.1016/j.yjmcc.2025.12.001","DOIUrl":"10.1016/j.yjmcc.2025.12.001","url":null,"abstract":"<div><div>In humans, the left atria (LA) and the left ventricle (LV) play distinct physiological roles and express sarcomeric proteins with chamber-specific patterns. Despite these important differences, most multi-chamber descriptions of the heart assume uniform myocardial properties. To facilitate a more accurate representation of cardiac function, we measured and compared the contractile properties of isolated skinned human LA and LV muscle fibers at 37 <span><math><mrow><mo>°</mo><mi>C</mi></mrow></math></span>. Our experimental measurements included the length-dependent activation (LDA) of force in the isometric steady state, the force response to small quick length changes, and tension redevelopment dynamics. The LV measurements display more pronounced LDA behavior compared to LA, whereas the LA dynamics is generally faster than LV.</div><div>To elucidate these differences mechanistically, we used the LA and LV experimental datasets to fit a biophysical model framework to produce a representative model for each chamber. Our Bayesian statistical approach aimed to maximize the objectivity of the model calibrations and to allow a systematic assessment of chamber-specific parameter differences. Passive mechanical properties emerge as the principal determinant of LDA behavior. However, variations in cross-bridge cycling kinetics account more significantly for LA/LV differences in the ATP consumption to produce a given isometric force.</div><div>These results constitute the first systematic biophysical comparison of LA and LV cardiomyocyte contraction mechanics in humans, paving the way to further investigation of their roles within the broader cardiovascular physiological context.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 64-77"},"PeriodicalIF":4.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1016/j.yjmcc.2025.12.002
Hanna J. Tadros , Diwakar Turaga , Kyle Hope , Joseph A. Spinner , Iki Adachi , Xiao Li , James F. Martin
Non-ischemic cardiomyopathy (NICM) is a devastating diagnosis with a wide array of phenotypes, ranging from mild cardiac hypertrophy to end-stage heart failure. Single-cell/nucleus RNA sequencing technologies have expanded and become a necessary tool to unravel the transcriptome across thousands to millions of cells. Studies incorporating these technologies to examine pediatric and adult myocardium have improved our understanding of underlying pathophysiology in cardiomyopathy, identified novel gene and genetic pathway associations, and paved the way for precision medicine therapeutics in cardiovascular medicine. We compiled the recent literature that showcase single cell/nucleus technologies in NICM in adult and pediatric populations and describe cell type-specific changes, ultimately setting the stage for future targeted gene manipulation/precision medicine.
{"title":"Single cell transcriptomic landscape of adult and pediatric non-ischemic cardiomyopathy","authors":"Hanna J. Tadros , Diwakar Turaga , Kyle Hope , Joseph A. Spinner , Iki Adachi , Xiao Li , James F. Martin","doi":"10.1016/j.yjmcc.2025.12.002","DOIUrl":"10.1016/j.yjmcc.2025.12.002","url":null,"abstract":"<div><div>Non-ischemic cardiomyopathy (NICM) is a devastating diagnosis with a wide array of phenotypes, ranging from mild cardiac hypertrophy to end-stage heart failure. Single-cell/nucleus RNA sequencing technologies have expanded and become a necessary tool to unravel the transcriptome across thousands to millions of cells. Studies incorporating these technologies to examine pediatric and adult myocardium have improved our understanding of underlying pathophysiology in cardiomyopathy, identified novel gene and genetic pathway associations, and paved the way for precision medicine therapeutics in cardiovascular medicine. We compiled the recent literature that showcase single cell/nucleus technologies in NICM in adult and pediatric populations and describe cell type-specific changes, ultimately setting the stage for future targeted gene manipulation/precision medicine.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 98-108"},"PeriodicalIF":4.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1016/j.yjmcc.2025.11.015
David Sánchez-López , David García-Vega , J.E. Viñuela , Isabel Ferreirós-Vidal , Diego Iglesias-Álvarez , José Manuel Martínez-Cereijo , Laura Reija-López , Ángel L. Fernández-González , José R. González-Juanatey , Sonia Eiras
{"title":"Corrigendum to ‘FABP4, marker of worse prognosis in cardiovascular disease, induces neutrophil’s proatherogenic phenotype which is modulated by semaglutide’ [Journal of Molecular and Cellular Cardiology volume 210 (2026) 12–27]","authors":"David Sánchez-López , David García-Vega , J.E. Viñuela , Isabel Ferreirós-Vidal , Diego Iglesias-Álvarez , José Manuel Martínez-Cereijo , Laura Reija-López , Ángel L. Fernández-González , José R. González-Juanatey , Sonia Eiras","doi":"10.1016/j.yjmcc.2025.11.015","DOIUrl":"10.1016/j.yjmcc.2025.11.015","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Page 63"},"PeriodicalIF":4.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1016/j.yjmcc.2025.11.014
Liang Zhao , Yuru Cao , Xianle Liu , Qing Yang , Zhelong Xu
While the ZIP family Zn2+ transporters such as ZIP2 and ZIP7 play critical roles in myocardial ischemia/reperfusion (I/R) injury by regulating Zn2+ homeostasis, little is known about the roles of the other ZIP family Zn2+ transporters in I/R injury. Here we report that ZIP14, a ZIP family Zn2+ transporter, contributes to the pathogenesis of myocardial I/R injury by controlling Fe2+ homeostasis.
Mouse hearts were subjected to I/R in vivo. Lipid peroxides were measured with C11-BODIPY and MDA. Infarct size was measured with the TTC staining. The cardiac-specific ZIP14 knockdown (AAV-shZIP14) and overexpression (AAV-ZIP14) mice were generated by adopting the AAV system. AAV-shZIP14 decreased but AAV-ZIP14 increased Fe2+ levels in cardiomyocytes. ZIP14 is upregulated at reperfusion, and AAV-shZIP14 reduced but AAV-ZIP14 enhanced ferroptosis caused by I/R. ZIP14 upregulation led to lysosomal lipid peroxidation in a Fe2+-dependent manner, which ultimately contributes to myocardium injury by causing lysosomal membrane permeabilization (LMP) and impairment of autophagic flux.
Our findings identify upregulation of ZIP14 leading to ferroptosis, LMP, and suppression of autophagic flux as a critical feature of myocardial I/R injury. Targeting cardiac ZIP14 upregulation may serve as a therapeutic strategy for the treatment of myocardial I/R injury.
{"title":"ZIP14 upregulation leads to ferroptosis and lysosomal dysfunction through intracellular iron overload and induces myocardial ischemia/reperfusion injury in mouse hearts","authors":"Liang Zhao , Yuru Cao , Xianle Liu , Qing Yang , Zhelong Xu","doi":"10.1016/j.yjmcc.2025.11.014","DOIUrl":"10.1016/j.yjmcc.2025.11.014","url":null,"abstract":"<div><div>While the ZIP family Zn<sup>2+</sup> transporters such as ZIP2 and ZIP7 play critical roles in myocardial ischemia/reperfusion (I/R) injury by regulating Zn<sup>2+</sup> homeostasis, little is known about the roles of the other ZIP family Zn<sup>2+</sup> transporters in I/R injury. Here we report that ZIP14, a ZIP family Zn<sup>2+</sup> transporter, contributes to the pathogenesis of myocardial I/R injury by controlling Fe<sup>2+</sup> homeostasis.</div><div>Mouse hearts were subjected to I/R in vivo. Lipid peroxides were measured with C11-BODIPY and MDA. Infarct size was measured with the TTC staining. The cardiac-specific ZIP14 knockdown (AAV-shZIP14) and overexpression (AAV-ZIP14) mice were generated by adopting the AAV system. AAV-shZIP14 decreased but AAV-ZIP14 increased Fe<sup>2+</sup> levels in cardiomyocytes. ZIP14 is upregulated at reperfusion, and AAV-shZIP14 reduced but AAV-ZIP14 enhanced ferroptosis caused by I/R. ZIP14 upregulation led to lysosomal lipid peroxidation in a Fe<sup>2+</sup>-dependent manner, which ultimately contributes to myocardium injury by causing lysosomal membrane permeabilization (LMP) and impairment of autophagic flux.</div><div>Our findings identify upregulation of ZIP14 leading to ferroptosis, LMP, and suppression of autophagic flux as a critical feature of myocardial I/R injury. Targeting cardiac ZIP14 upregulation may serve as a therapeutic strategy for the treatment of myocardial I/R injury.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 78-91"},"PeriodicalIF":4.7,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145634644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1016/j.yjmcc.2025.11.013
Mohit M. Hulsurkar , Isabelle Ong , Joshua A. Keefe , Issam H. Abu-Taha , Dobromir Dobrev , Xander H.T. Wehrens
Cyclic adenosine monophosphate (cAMP) is a critical second messenger in cardiomyocytes, regulating essential cellular functions. Upon G-protein-coupled receptor stimulation, adenylyl cyclase (AC) synthesizes cAMP, which phosphodiesterase (PDE) enzymes subsequently degrade. Recent studies challenge the traditional view of uniform cAMP signaling, revealing nanodomain-specific regulation within cardiomyocytes. This localized cAMP signaling modulates key Ca2+-handling proteins, including ryanodine receptor type-2 (RyR2), through channel-bound protein kinases and PDEs. Additionally, nucleoside-diphosphate kinases (NDPKs), particularly NDPK-C, contribute to cAMP synthesis and RyR2 regulation. Elevated NDPK-C levels in failing hearts correlate with increased cAMP levels, enhanced sarcoplasmic reticulum Ca2+ release, and cardiac arrhythmias. Furthermore, cAMP influences the expression of Ca2+-handling proteins. This review examines the mechanisms governing cAMP levels in the sarcoplasmic reticulum nanodomain and their role in regulating RyR2 function in healthy and diseased hearts.
{"title":"Cyclic AMP-dependent regulation of ryanodine receptors in healthy and diseased hearts","authors":"Mohit M. Hulsurkar , Isabelle Ong , Joshua A. Keefe , Issam H. Abu-Taha , Dobromir Dobrev , Xander H.T. Wehrens","doi":"10.1016/j.yjmcc.2025.11.013","DOIUrl":"10.1016/j.yjmcc.2025.11.013","url":null,"abstract":"<div><div>Cyclic adenosine monophosphate (cAMP) is a critical second messenger in cardiomyocytes, regulating essential cellular functions. Upon G-protein-coupled receptor stimulation, adenylyl cyclase (AC) synthesizes cAMP, which phosphodiesterase (PDE) enzymes subsequently degrade. Recent studies challenge the traditional view of uniform cAMP signaling, revealing nanodomain-specific regulation within cardiomyocytes. This localized cAMP signaling modulates key Ca<sup>2+</sup>-handling proteins, including ryanodine receptor type-2 (RyR2), through channel-bound protein kinases and PDEs. Additionally, nucleoside-diphosphate kinases (NDPKs), particularly NDPK-C, contribute to cAMP synthesis and RyR2 regulation. Elevated NDPK-C levels in failing hearts correlate with increased cAMP levels, enhanced sarcoplasmic reticulum Ca<sup>2+</sup> release, and cardiac arrhythmias. Furthermore, cAMP influences the expression of Ca<sup>2+</sup>-handling proteins. This review examines the mechanisms governing cAMP levels in the sarcoplasmic reticulum nanodomain and their role in regulating RyR2 function in healthy and diseased hearts.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 53-62"},"PeriodicalIF":4.7,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145634615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1016/j.yjmcc.2025.11.011
Xinyu Song , Dan Yang , Zhe Sun , Shumin Yin , Chenhao Wang , Wei Hou , Yu Sun , Fen Zheng , Juejin Wang
Aims
Myocardial hypertrophy, a pathological adaptation to chronic stress, predisposes to heart failure through dysregulated calcium handling. Alternative splicing (AS) of CaV1.2 calcium channel participates in myocardial hypertrophy, and RNA-binding motif protein 20 (Rbm20) regulates CaV1.2 AS. Moreover, impaired retinoic acid receptor β (RARβ) is implicated in cardiac pathologies, but its roles in handling cardiac intracellular calcium during myocardial hypertrophy remain unknown. Here, we explore whether impaired RARβ exacerbates cardiac pathological remodeling by disrupting Rbm20-mediated CaV1.2 AS.
Methods and results
Transverse aortic constriction (TAC) and isoproterenol (ISO)-induced murine hypertrophic hearts showed increased CaV1.2 alternative exon 9* (CaV1.2E9*), accompanied with reduced Rbm20 expression. Rbm20 downregulated CaV1.2 exon 9* in cardiomyocytes. Bioinformatic analysis of human hypertrophic cardiomyopathy datasets revealed impaired RA signaling, marked by RARβ downregulation, which was confirmed in TAC hearts and ISO-treated neonatal rat ventricular myocytes (NRVMs). RARβ knockdown increased the proportion of CaV1.2E9* channels and K+-triggered intracellular Ca2+ concentration ([Ca2+]i) in NRVMs. Chromatin immunoprecipitation and dual-luciferase assays identified that RARβ directly binds to Rbm20 promoter region, and adapalene (ADP), a selective RARβ agonist, increased their binding affinity. For clinical relevance, ADP restored Rbm20 expression, normalized CaV1.2E9* splicing, decreased K+-triggered [Ca2+]i, and attenuated cardiomyocyte hypertrophy. In vivo, ADP administration alleviated myocardial hypertrophy in TAC mice.
Conclusion
Our findings reveal impaired RARβ drives CaV1.2 aberrant splicing by downregulating Rbm20, establishing a feedforward loop of intracellular calcium imbalances and hypertrophic remodeling. Significantly, ADP restores CaV1.2 AS and intracellular calcium homeostasis by activating RARβ in cardiomyocytes, highlighting a novel therapeutic approach for myocardial hypertrophy.
{"title":"Impaired retinoic acid signaling mediated Rbm20 downregulation induces aberrant splicing of CaV1.2 calcium channel: implications in myocardial hypertrophy","authors":"Xinyu Song , Dan Yang , Zhe Sun , Shumin Yin , Chenhao Wang , Wei Hou , Yu Sun , Fen Zheng , Juejin Wang","doi":"10.1016/j.yjmcc.2025.11.011","DOIUrl":"10.1016/j.yjmcc.2025.11.011","url":null,"abstract":"<div><h3>Aims</h3><div>Myocardial hypertrophy, a pathological adaptation to chronic stress, predisposes to heart failure through dysregulated calcium handling. Alternative splicing (AS) of Ca<sub>V</sub>1.2 calcium channel participates in myocardial hypertrophy, and RNA-binding motif protein 20 (Rbm20) regulates Ca<sub>V</sub>1.2 AS. Moreover, impaired retinoic acid receptor β (RARβ) is implicated in cardiac pathologies, but its roles in handling cardiac intracellular calcium during myocardial hypertrophy remain unknown. Here, we explore whether impaired RARβ exacerbates cardiac pathological remodeling by disrupting Rbm20-mediated Ca<sub>V</sub>1.2 AS.</div></div><div><h3>Methods and results</h3><div>Transverse aortic constriction (TAC) and isoproterenol (ISO)-induced murine hypertrophic hearts showed increased Ca<sub>V</sub>1.2 alternative exon 9* (Ca<sub>V</sub>1.2<sub>E9</sub><sub>*</sub>), accompanied with reduced Rbm20 expression. Rbm20 downregulated Ca<sub>V</sub>1.2 exon 9* in cardiomyocytes. Bioinformatic analysis of human hypertrophic cardiomyopathy datasets revealed impaired RA signaling, marked by RARβ downregulation, which was confirmed in TAC hearts and ISO-treated neonatal rat ventricular myocytes (NRVMs). RARβ knockdown increased the proportion of Ca<sub>V</sub>1.2<sub>E9</sub><sub>*</sub> channels and K<sup>+</sup>-triggered intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) in NRVMs. Chromatin immunoprecipitation and dual-luciferase assays identified that RARβ directly binds to <em>Rbm20</em> promoter region, and adapalene (ADP), a selective RARβ agonist, increased their binding affinity. For clinical relevance, ADP restored Rbm20 expression, normalized Ca<sub>V</sub>1.2<sub>E9</sub><sub>*</sub> splicing, decreased K<sup>+</sup>-triggered [Ca<sup>2+</sup>]<sub>i</sub>, and attenuated cardiomyocyte hypertrophy. In vivo, ADP administration alleviated myocardial hypertrophy in TAC mice.</div></div><div><h3>Conclusion</h3><div>Our findings reveal impaired RARβ drives Ca<sub>V</sub>1.2 aberrant splicing by downregulating Rbm20, establishing a feedforward loop of intracellular calcium imbalances and hypertrophic remodeling. Significantly, ADP restores Ca<sub>V</sub>1.2 AS and intracellular calcium homeostasis by activating RARβ in cardiomyocytes, highlighting a novel therapeutic approach for myocardial hypertrophy.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 28-42"},"PeriodicalIF":4.7,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.yjmcc.2025.11.009
Frank J. Raucci , Adolfo G. Mauro , Edward J. Lesnefsky , Clive M. Baumgarten
<div><h3>Aims</h3><div>We previously demonstrated that bacterial sphingomyelinase (SMase), which converts plasmalemmal sphingomyelin to long-chain ceramides, activates the swelling-activated chloride current (<em>I</em><sub><em>Cl,swell</em></sub>) in rabbit ventricular myocytes in a reactive oxygen (ROS)-dependent manner under isosmotic conditions. Ceramides can be converted to sphingosine by ceramidase and, in turn, phosphorylated by sphingosine kinase to yield sphingosine-1-phosphate (S1P), which binds to multiple cytoplasmic targets and activates S1P receptors via inside-out transport. This study was designed to determine the cellular source of ROS production elicited by SMase, the sphingolipid species responsible, and thereby, the mechanism of activation of <em>I</em><sub><em>Cl,swell</em></sub> by sphingolipids.</div></div><div><h3>Methods and results</h3><div>Whole-cell patch clamp experiments were conducted using freshly isolated rabbit ventricular myocytes. Inhibition of ceramidase with D-<em>erythro</em>-MAPP, which increases the concentration of endogenous ceramides in the cell membrane, prevented activation of <em>I</em><sub><em>Cl,swell</em></sub> upon exposure to SMase. Similarly, inhibition of sphingosine kinase with DL-<em>threo</em>-dihydrosphingosine to prevent SIP formation by phosphorylation of sphingosine also completely inhibited SMase-induced Cl<sup>−</sup> current. In contrast, addition of S1P to the bath solution elicited <em>I</em><sub><em>Cl,swell</em></sub>. ROS generated by both NADPH oxidase 2 (NOX2) and mitochondria previously were implicated in triggering <em>I</em><sub><em>Cl,swell</em></sub>. SMase-induced <em>I</em><sub><em>Cl,swell</em></sub> activation was abrogated by blocking mitochondrial electron transport at Complex I with rotenone but was insensitive to blockade of NOX2 with either apocynin or gp91ds-tat. Moreover, diazoxide, which augments mitochondrial ROS production, evoked <em>I</em><sub><em>Cl,swell</em></sub>, and 5-HD, an inhibitor of this pathway, reversed the SMase and diazoxide-induced currents. Flow cytometry using C-H<sub>2</sub>DCFDA-AM to assess cytoplasmic ROS in HL-1 myocytes confirmed the effects of the interventions on ROS production.</div></div><div><h3>Conclusions</h3><div>Taken together, these data suggest S1P is the sphingolipid that triggers <em>I</em><sub><em>Cl,swell</em></sub> in cardiomyocyte, and activation of <em>I</em><sub><em>Cl,swell</em></sub> by SMase and S1P is due to ROS produced by mitochondria and appears independent of NOX2.</div></div><div><h3>Translational perspective</h3><div><em>I</em><sub><em>Cl,swell</em></sub> modulates apoptosis, cell volume, action potential duration, and participation in mechanoelectrical feedback in cardiomyocytes. Persistent activation of <em>I</em><sub><em>Cl,swell</em></sub> is seen in several forms of cardiac disease, including dilated cardiomyopathy [<span><span>1</span></span>] and models of heart failure [<span><span>2</span></span
目的：我们之前已经证明，细菌鞘磷脂酶（SMase）可以将血浆鞘磷脂转化为长链神经酰胺，在等渗条件下以活性氧（ROS）依赖的方式激活兔心室肌细胞中肿胀激活的氯电流（ICl，肿胀）。神经酰胺可以通过神经酰胺酶转化为鞘氨醇，然后通过鞘氨醇激酶磷酸化生成鞘氨醇-1-磷酸（S1P），其结合多个细胞质靶点并通过内向外运输激活S1P受体。本研究旨在确定由鞘脂类SMase引起的ROS产生的细胞来源，从而确定鞘脂激活ICl、膨胀的机制。方法和结果：采用新鲜分离的兔心室肌细胞进行全细胞膜片钳实验。用d - red - mapp抑制神经酰胺酶，增加细胞膜内源性神经酰胺的浓度，阻止暴露于SMase后ICl的激活和肿胀。同样，用dl -三氢鞘氨醇抑制鞘氨醇激酶，通过鞘氨醇磷酸化阻止SIP的形成，也完全抑制了smase诱导的Cl-电流。相反，在浴液中加入S1P会引起ICl，膨胀。由NADPH氧化酶2 （NOX2）和线粒体产生的ROS先前涉及触发ICl，肿胀。smase诱导的ICl，肿胀激活可以通过鱼藤酮阻断复合物I的线粒体电子传递来消除，但对夹带素或gp91ds-tat阻断NOX2不敏感。此外，增加线粒体ROS产生的二氮氧化物，可诱发ICl、swell和5-HD（该途径的抑制剂），逆转SMase和二氮氧化物诱导的电流。使用C-H2DCFDA-AM流式细胞术评估HL-1肌细胞的细胞质ROS，证实了干预对ROS产生的影响。结论：综上所述，这些数据表明S1P是触发心肌细胞ICl、肿胀的鞘脂，SMase和S1P对ICl、肿胀的激活是由于线粒体产生的ROS，并且与NOX2无关。翻译角度：ICl，肿胀调节心肌细胞的凋亡，细胞体积，动作电位持续时间和参与机电反馈。ICl持续激活，肿胀可见于多种心脏疾病，包括扩张型心肌病[1]和心力衰竭模型[2]。此外，它还与代谢综合征和随后的2型糖尿病（DM2）发展有关。这意味着一种复杂的关系，其中可能既有对受损心肌细胞的直接影响，也有对心血管系统的间接影响，导致慢性细胞应激，如在DM2中所见。该报告首次证明，S1P通过破坏线粒体呼吸链导致ROS释放来增强心肌细胞的ICl、肿胀激活。这为治疗以鞘脂代谢改变为特征的扩张型心肌病或代谢综合征等心血管疾病提供了潜在的治疗靶点。
{"title":"Sphingosine-1-phosphate activates ICl,swell in ventricular myocytes via mitochondrial reactive oxygen production","authors":"Frank J. Raucci , Adolfo G. Mauro , Edward J. Lesnefsky , Clive M. Baumgarten","doi":"10.1016/j.yjmcc.2025.11.009","DOIUrl":"10.1016/j.yjmcc.2025.11.009","url":null,"abstract":"<div><h3>Aims</h3><div>We previously demonstrated that bacterial sphingomyelinase (SMase), which converts plasmalemmal sphingomyelin to long-chain ceramides, activates the swelling-activated chloride current (<em>I</em><sub><em>Cl,swell</em></sub>) in rabbit ventricular myocytes in a reactive oxygen (ROS)-dependent manner under isosmotic conditions. Ceramides can be converted to sphingosine by ceramidase and, in turn, phosphorylated by sphingosine kinase to yield sphingosine-1-phosphate (S1P), which binds to multiple cytoplasmic targets and activates S1P receptors via inside-out transport. This study was designed to determine the cellular source of ROS production elicited by SMase, the sphingolipid species responsible, and thereby, the mechanism of activation of <em>I</em><sub><em>Cl,swell</em></sub> by sphingolipids.</div></div><div><h3>Methods and results</h3><div>Whole-cell patch clamp experiments were conducted using freshly isolated rabbit ventricular myocytes. Inhibition of ceramidase with D-<em>erythro</em>-MAPP, which increases the concentration of endogenous ceramides in the cell membrane, prevented activation of <em>I</em><sub><em>Cl,swell</em></sub> upon exposure to SMase. Similarly, inhibition of sphingosine kinase with DL-<em>threo</em>-dihydrosphingosine to prevent SIP formation by phosphorylation of sphingosine also completely inhibited SMase-induced Cl<sup>−</sup> current. In contrast, addition of S1P to the bath solution elicited <em>I</em><sub><em>Cl,swell</em></sub>. ROS generated by both NADPH oxidase 2 (NOX2) and mitochondria previously were implicated in triggering <em>I</em><sub><em>Cl,swell</em></sub>. SMase-induced <em>I</em><sub><em>Cl,swell</em></sub> activation was abrogated by blocking mitochondrial electron transport at Complex I with rotenone but was insensitive to blockade of NOX2 with either apocynin or gp91ds-tat. Moreover, diazoxide, which augments mitochondrial ROS production, evoked <em>I</em><sub><em>Cl,swell</em></sub>, and 5-HD, an inhibitor of this pathway, reversed the SMase and diazoxide-induced currents. Flow cytometry using C-H<sub>2</sub>DCFDA-AM to assess cytoplasmic ROS in HL-1 myocytes confirmed the effects of the interventions on ROS production.</div></div><div><h3>Conclusions</h3><div>Taken together, these data suggest S1P is the sphingolipid that triggers <em>I</em><sub><em>Cl,swell</em></sub> in cardiomyocyte, and activation of <em>I</em><sub><em>Cl,swell</em></sub> by SMase and S1P is due to ROS produced by mitochondria and appears independent of NOX2.</div></div><div><h3>Translational perspective</h3><div><em>I</em><sub><em>Cl,swell</em></sub> modulates apoptosis, cell volume, action potential duration, and participation in mechanoelectrical feedback in cardiomyocytes. Persistent activation of <em>I</em><sub><em>Cl,swell</em></sub> is seen in several forms of cardiac disease, including dilated cardiomyopathy [<span><span>1</span></span>] and models of heart failure [<span><span>2</span></span","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 18-27"},"PeriodicalIF":4.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.yjmcc.2025.11.012
Shivani Sethi , Isaiah Cheong , Carol T. Bussey , Daryl O. Schwenke , Jeffrey R. Erickson , Colin H. Brown , Regis R. Lamberts
Diabetic heart disease is a leading cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). A major yet frequently under-recognized component of diabetic heart disease is cardiac autonomic neuropathy (CAN), a condition characterized by dysregulated sympathetic and parasympathetic drive to the heart.
Current pharmacological treatments for diabetic CAN are often ineffective, having been extrapolated from other health conditions. These therapies predominantly target the peripheral symptoms of elevated sympathetic activity, whilst largely neglecting its origins in sympathoexcitatory regions of the central autonomic network. Sympathetic control of cardiac function originates from the hypothalamus, medulla oblongata, midbrain, and pons, and is relayed through the intermediolateral cell column of the thoracic spinal cord and the intrinsic cardiac nervous system. Targeting the central autonomic network to modulate cardiac sympathetic drive presents a promising novel therapeutic avenue for the treatment of diabetic CAN.
This review briefly summarizes established knowledge regarding the pathophysiology and management of diabetic CAN, and the implications of recent findings of increased neuronal activation in central sympathoregulatory regions early in the development of T2DM. Increased cardiac sympathetic in the intital stages of T2DM might represent a novel therapeutic target to reduce the impact of CAN and thereby improve outcomes in patients with T2DM.
{"title":"Central regulation of the heart in type 2 diabetes mellitus","authors":"Shivani Sethi , Isaiah Cheong , Carol T. Bussey , Daryl O. Schwenke , Jeffrey R. Erickson , Colin H. Brown , Regis R. Lamberts","doi":"10.1016/j.yjmcc.2025.11.012","DOIUrl":"10.1016/j.yjmcc.2025.11.012","url":null,"abstract":"<div><div>Diabetic heart disease is a leading cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). A major yet frequently under-recognized component of diabetic heart disease is cardiac autonomic neuropathy (CAN), a condition characterized by dysregulated sympathetic and parasympathetic drive to the heart.</div><div>Current pharmacological treatments for diabetic CAN are often ineffective, having been extrapolated from other health conditions. These therapies predominantly target the peripheral symptoms of elevated sympathetic activity, whilst largely neglecting its origins in sympathoexcitatory regions of the central autonomic network. Sympathetic control of cardiac function originates from the hypothalamus, medulla oblongata, midbrain, and pons, and is relayed through the intermediolateral cell column of the thoracic spinal cord and the intrinsic cardiac nervous system. Targeting the central autonomic network to modulate cardiac sympathetic drive presents a promising novel therapeutic avenue for the treatment of diabetic CAN.</div><div>This review briefly summarizes established knowledge regarding the pathophysiology and management of diabetic CAN, and the implications of recent findings of increased neuronal activation in central sympathoregulatory regions early in the development of T2DM. Increased cardiac sympathetic in the intital stages of T2DM might represent a novel therapeutic target to reduce the impact of CAN and thereby improve outcomes in patients with T2DM.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 43-52"},"PeriodicalIF":4.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1016/j.yjmcc.2025.11.008
Jacob A. Miller , Nicolae Moise , Mario J. Mendez , Seth H. Weinberg
Heart failure (HF) is the presentation of mechanical pump dysfunction, with HF patients facing increased risk of sudden cardiac death predominantly driven by ventricular arrhythmias. At the cellular level, HF is associated with remodeling of ionic currents and fluxes, as well as chronic activation of -adrenergic signaling pathways, ultimately resulting in pathological changes in action potential and intracellular calcium transient characteristics. However, it is challenging to understand the mechanistic underpinnings of HF and associated arrhythmias across diverse populations, due to both inter-individual variability and variability in disease-associated remodeling. In this study, we perform numerical simulations of a model of human ventricular myocytes, utilizing a novel population approach to distinctly represent the variability in both intrinsic cellular properties and properties of HF-associated ionic and -adrenergic signaling remodeling, to predict key outcomes of arrhythmia susceptibility and the presentation of the HF phenotype. We highlight the cellular properties and remodeling leading to both arrhythmia and the HF phenotype, noting key similarities and differences. Critically, we find that the relationship between intrinsic cellular properties and outcome (i.e., arrhythmia susceptibility or the HF phenotype) can be different than the relationship between remodeling severity and outcome, with the expression levels and remodeling severity of inwardly rectifying potassium current () and the sodium–calcium exchanger () as notable examples. Finally, we find that upregulation of specific -adrenergic signaling molecules are predicted to be protective against arrhythmia. Overall, our study presents a novel approach to investigate inter-individual and disease variability and identifies how the interplay between the intrinsic variability in electrophysiology and heart failure-associated remodeling influences arrhythmias in the setting of human heart failure.
{"title":"Interplay between variability in intrinsic cellular properties and heart failure-associated remodeling in a simulated population with human heart failure","authors":"Jacob A. Miller , Nicolae Moise , Mario J. Mendez , Seth H. Weinberg","doi":"10.1016/j.yjmcc.2025.11.008","DOIUrl":"10.1016/j.yjmcc.2025.11.008","url":null,"abstract":"<div><div>Heart failure (HF) is the presentation of mechanical pump dysfunction, with HF patients facing increased risk of sudden cardiac death predominantly driven by ventricular arrhythmias. At the cellular level, HF is associated with remodeling of ionic currents and fluxes, as well as chronic activation of <span><math><mi>β</mi></math></span>-adrenergic signaling pathways, ultimately resulting in pathological changes in action potential and intracellular calcium transient characteristics. However, it is challenging to understand the mechanistic underpinnings of HF and associated arrhythmias across diverse populations, due to both inter-individual variability and variability in disease-associated remodeling. In this study, we perform numerical simulations of a model of human ventricular myocytes, utilizing a novel population approach to distinctly represent the variability in both intrinsic cellular properties and properties of HF-associated ionic and <span><math><mi>β</mi></math></span>-adrenergic signaling remodeling, to predict key outcomes of arrhythmia susceptibility and the presentation of the HF phenotype. We highlight the cellular properties and remodeling leading to both arrhythmia and the HF phenotype, noting key similarities and differences. Critically, we find that the relationship between intrinsic cellular properties and outcome (i.e., arrhythmia susceptibility or the HF phenotype) can be different than the relationship between remodeling severity and outcome, with the expression levels and remodeling severity of inwardly rectifying potassium current (<span><math><msub><mrow><mi>I</mi></mrow><mrow><mi>K</mi><mn>1</mn></mrow></msub></math></span>) and the sodium–calcium exchanger (<span><math><msub><mrow><mi>I</mi></mrow><mrow><mi>N</mi><mi>a</mi><mi>C</mi><mi>a</mi></mrow></msub></math></span>) as notable examples. Finally, we find that upregulation of specific <span><math><mi>β</mi></math></span>-adrenergic signaling molecules are predicted to be protective against arrhythmia. Overall, our study presents a novel approach to investigate inter-individual and disease variability and identifies how the interplay between the intrinsic variability in electrophysiology and heart failure-associated remodeling influences arrhythmias in the setting of human heart failure.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 1-17"},"PeriodicalIF":4.7,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145546585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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