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}
Stretch-activated ion channels (SACs) mediate mechano-electric feedback in cardiomyocytes by coupling mechanical and electrical activity. While SACs activation can induce pro-arrhythmic effects at the cellular level, its impact on tissue-level arrhythmias remains poorly understood. Particularly unclear are the specific stretch characteristics that promote arrhythmogenesis, a knowledge gap largely due to limited experimental control over these parameters.
We investigated how SACs activation affects excitation-wave propagation in simulated ventricular tissue and identified parameters promoting arrhythmias, with relevance to commotio cordis, in which a chest impact can trigger ventricular arrhythmias and sudden cardiac death. Our approach employed a validated human ventricular action potential model incorporating three types of SACs (non-selective, potassium-selective, and calcium-selective) applied to a two-dimensional tissue framework. Through systematic multiparameter analysis, we examined the effects of stretch stimulus parameters (amplitude, duration, timing), spatial characteristics (area, location, gradient), and tissue properties (size, conduction velocity).
Our simulations revealed that re-entry arises from interactions between stretch-induced depolarization waves and repolarization tails of preceding excitation waves. Acute supra-threshold stretch (i.e., stretch able to trigger an action potential) initiated re-entries with increased likelihood when path lengths were longer and when stretched regions were closer to non-conducting borders oriented perpendicular to the line of block. Furthermore, stretch amplitude gradients attenuated pro-arrhythmic effects, while sustained sub-threshold stretch either reduced conduction velocity or caused conduction block. This in silico analysis demonstrates that tissue-level proarrhythmic effects of stretch depend on complex interactions between stretch stimulus characteristics, spatial parameters, and tissue properties.
{"title":"Spatiotemporal determinants of stretch-activated channel-induced re-entry in ventricular tissue: An in-silico study","authors":"Melania Buonocunto , Tammo Delhaas , Aurore Lyon , Jordi Heijman , Joost Lumens","doi":"10.1016/j.yjmcc.2025.11.007","DOIUrl":"10.1016/j.yjmcc.2025.11.007","url":null,"abstract":"<div><div>Stretch-activated ion channels (SACs) mediate mechano-electric feedback in cardiomyocytes by coupling mechanical and electrical activity. While SACs activation can induce pro-arrhythmic effects at the cellular level, its impact on tissue-level arrhythmias remains poorly understood. Particularly unclear are the specific stretch characteristics that promote arrhythmogenesis, a knowledge gap largely due to limited experimental control over these parameters.</div><div>We investigated how SACs activation affects excitation-wave propagation in simulated ventricular tissue and identified parameters promoting arrhythmias, with relevance to commotio cordis, in which a chest impact can trigger ventricular arrhythmias and sudden cardiac death. Our approach employed a validated human ventricular action potential model incorporating three types of SACs (non-selective, potassium-selective, and calcium-selective) applied to a two-dimensional tissue framework. Through systematic multiparameter analysis, we examined the effects of stretch stimulus parameters (amplitude, duration, timing), spatial characteristics (area, location, gradient), and tissue properties (size, conduction velocity).</div><div>Our simulations revealed that re-entry arises from interactions between stretch-induced depolarization waves and repolarization tails of preceding excitation waves. Acute supra-threshold stretch (i.e., stretch able to trigger an action potential) initiated re-entries with increased likelihood when path lengths were longer and when stretched regions were closer to non-conducting borders oriented perpendicular to the line of block. Furthermore, stretch amplitude gradients attenuated pro-arrhythmic effects, while sustained sub-threshold stretch either reduced conduction velocity or caused conduction block. This in silico analysis demonstrates that tissue-level proarrhythmic effects of stretch depend on complex interactions between stretch stimulus characteristics, spatial parameters, and tissue properties.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 150-164"},"PeriodicalIF":4.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556897","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}
Cardiac organoids serve as a valuable model for studying physiological and pathophysiological processes affecting heart rate and rhythm. Multi-electrode arrays (MEA) are widely used for high-throughput electrophysiological assessments. Despite the widespread use of MEA technology in cardiac research, current analysis tools primarily focus on one dimensional (1D) electrophysiological biomarkers and on average interbeat intervals.
We aim to develop innovative algorithms to expand cardiac electrophysiological analysis by enabling standardized biomarker calculation, spatiotemporal biomarker dynamics assessment, and comprehensive beat rate variability (BRV) analysis of cardiac organoids.
Electrograms were recorded from spontaneously beating cardiac organoids (n = 15), generated from human-induced pluripotent stem cell-derived cardiomyocytes, using 8 × 8 electrode MEA plates. Novel algorithms were developed for R-, S-, and T-peak detection, as well as advanced two dimensions (2D) electrical signal processing of these biomarkers. All algorithms were implemented on the PhysioMEA platform.
Biomarker distributions in cardiac organoids exhibited a high degree of similarity in 1D under basal conditions, as indicated by their coefficients of variation (p-value >0.209). In 2D, R- to S-peaks amplitude, maximal slope, peak-to-peak duration and field potential duration coefficients of variation were 39.04 %, 46.95 %, 22.76 %, and 25.00 %, respectively. Additionally, comprehensive analysis of BRV revealed primarily very low frequency content (63.42 %) in cardiac organoid interbeat interval spectra compared to low- and high-frequency components (15.57 % and 21.02 %, respectively).
Thus, 1D and 2D electrophysiological analysis and BRV assessment of cardiac organoids using the open-source PhysioMEA platform, shows high similarities in 1D, but not in 2D, between different physiological biomarkers.
{"title":"PhysioMEA: Signal processing platform for rate and rhythm analysis of multi-electrode array cardiac electrophysiological recordings","authors":"Ido Weiser-Bitoun , Savyon Mazgaoker , Shani Assayag , Moran Davoodi , Alexandra Alexandrovich , Yael Yaniv","doi":"10.1016/j.yjmcc.2025.11.006","DOIUrl":"10.1016/j.yjmcc.2025.11.006","url":null,"abstract":"<div><div>Cardiac organoids serve as a valuable model for studying physiological and pathophysiological processes affecting heart rate and rhythm. Multi-electrode arrays (MEA) are widely used for high-throughput electrophysiological assessments. Despite the widespread use of MEA technology in cardiac research, current analysis tools primarily focus on one dimensional (1D) electrophysiological biomarkers and on average interbeat intervals.</div><div>We aim to develop innovative algorithms to expand cardiac electrophysiological analysis by enabling standardized biomarker calculation, spatiotemporal biomarker dynamics assessment, and comprehensive beat rate variability (BRV) analysis of cardiac organoids.</div><div>Electrograms were recorded from spontaneously beating cardiac organoids (<em>n</em> = 15), generated from human-induced pluripotent stem cell-derived cardiomyocytes, using 8 × 8 electrode MEA plates. Novel algorithms were developed for R-, S-, and T-peak detection, as well as advanced two dimensions (2D) electrical signal processing of these biomarkers. All algorithms were implemented on the PhysioMEA platform.</div><div>Biomarker distributions in cardiac organoids exhibited a high degree of similarity in 1D under basal conditions, as indicated by their coefficients of variation (<em>p</em>-value >0.209). In 2D, R- to S-peaks amplitude, maximal slope, peak-to-peak duration and field potential duration coefficients of variation were 39.04 %, 46.95 %, 22.76 %, and 25.00 %, respectively. Additionally, comprehensive analysis of BRV revealed primarily very low frequency content (63.42 %) in cardiac organoid interbeat interval spectra compared to low- and high-frequency components (15.57 % and 21.02 %, respectively).</div><div>Thus, 1D and 2D electrophysiological analysis and BRV assessment of cardiac organoids using the open-source PhysioMEA platform, shows high similarities in 1D, but not in 2D, between different physiological biomarkers.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 137-149"},"PeriodicalIF":4.7,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556912","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 : 2025-11-15DOI: 10.1016/j.yjmcc.2025.11.004
Dogacan Yücel , Calvin Smith , Natalia Ferreira de Araujo , Fernando Souza-Neto , Upendra Chalise , Grace Schuler , Bayardo I. Garay , Jennifer L. Mikkila , Omar Atef Abdelhamid Mahmoud , Pratima Mandal , Rita C.R. Perlingeiro , Jop H. van Berlo
Summary (145)
Adult cardiomyocytes exit the cell cycle soon after birth, although this shift can be reversed by molecular interventions. To identify novel regulators of cardiomyocyte proliferation, we performed a comparative transcriptomic analysis of actively proliferating and non-proliferating cardiomyocytes across key pre-and post-natal developmental timepoints. Integration of bioinformatics analyses with a functional screen of 238 differentially expressed genes identified WWC2 as a regulator of cell cycle exit. Inhibition of Wwc2 induced cell cycle entry with completion of mitosis and cytokinesis, while overexpression of WWC2 induced cell cycle exit. Moreover, inhibition of Wwc2 resulted in dedifferentiation of cardiomyocytes with reduced expression of sarcomeric and calcium handling genes. Mechanistically, WWC2 binds to 14–3-3 and regulates YAP phosphorylation and expression. In vivo, deletion of Wwc2 stimulated cardiac regeneration after myocardial infarction. These results identify WWC2 as an important regulator of cardiomyocyte cell cycle exit and initiation of the maturation process.
{"title":"Small-scale siRNA screen reveals WWC2 as a novel regulator of cardiomyocyte mitosis","authors":"Dogacan Yücel , Calvin Smith , Natalia Ferreira de Araujo , Fernando Souza-Neto , Upendra Chalise , Grace Schuler , Bayardo I. Garay , Jennifer L. Mikkila , Omar Atef Abdelhamid Mahmoud , Pratima Mandal , Rita C.R. Perlingeiro , Jop H. van Berlo","doi":"10.1016/j.yjmcc.2025.11.004","DOIUrl":"10.1016/j.yjmcc.2025.11.004","url":null,"abstract":"<div><h3>Summary (145)</h3><div>Adult cardiomyocytes exit the cell cycle soon after birth, although this shift can be reversed by molecular interventions. To identify novel regulators of cardiomyocyte proliferation, we performed a comparative transcriptomic analysis of actively proliferating and non-proliferating cardiomyocytes across key pre-and post-natal developmental timepoints. Integration of bioinformatics analyses with a functional screen of 238 differentially expressed genes identified WWC2 as a regulator of cell cycle exit. Inhibition of <em>Wwc2</em> induced cell cycle entry with completion of mitosis and cytokinesis, while overexpression of WWC2 induced cell cycle exit. Moreover, inhibition of <em>Wwc2</em> resulted in dedifferentiation of cardiomyocytes with reduced expression of sarcomeric and calcium handling genes. Mechanistically, WWC2 binds to 14–3-3 and regulates YAP phosphorylation and expression. In vivo, deletion of <em>Wwc2</em> stimulated cardiac regeneration after myocardial infarction. These results identify WWC2 as an important regulator of cardiomyocyte cell cycle exit and initiation of the maturation process.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 127-136"},"PeriodicalIF":4.7,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145540996","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 : 2025-11-15DOI: 10.1016/j.yjmcc.2025.11.005
Min Zhang , Chen Chen , Xinxing Liu , Zhou Zhou , Gen Li , Xiangrui Jiang , Jingshan Shen , Hualiang Jiang , Zheng Wen , Yan Liu , Dao Wen Wang
Background
Our prior clinical studies established a positive correlation between sEH activity and mortality in heart failure with preserved ejection fraction (HFpEF), the pathophysiological role of the sEH/EET axis in metabolic stress (obesity and metabolic syndrome) and mechanical stress (hypertension)-induced HFpEF remains unknown.
Methods
We elucidated the function and mechanism of sEH and EETs in ‘two-hit’ (high-fat diet and inhibition of constitutive nitric oxide synthase using Nω-nitrol-arginine methyl ester) HFpEF animal model. Langendorff system was applied to isolate cardiomyocytes from HFpEF mice. Recombinant adeno-associated virus type 9 was used to deliver cytochrome P450 2E1 (CYP2E1) to cardiac-specific knockout sEH HFpEF mice through the tail vein.
Results
sEH activity and expression were upregulated, while EETs levels were reduced in the hearts and isolated cardiomyocytes from HFpEF mice or cardiomyocyte cell lines pretreated with palmitate acid and Nω-nitrol-arginine methyl ester. Desuccinylation, a posttranslational modification of sEH (K)191, maintained the activity of sEH in HFpEF. Genetic or pharmacological inhibition of the sEH restored the levels of EETs and ameliorated HFpEF phenotype with significantly improved diastolic dysfunction and cardiac remodeling. Mechanically, sEH inhibitors (sEHIs) targeted CYP2E1, a crucial CYP450 enzyme, to inhibit reactive oxygen species (ROS) and fatty acid uptake. Overexpressing CYP2E1 abolished the protective effects of sEH inhibition in vivo.
Conclusions
These findings confirmed sEH as a therapeutic target in metabolic stress and mechanical stress-induced HFpEF mice model via the cardioprotective effects of EETs, which were mediated partially by targeting CYP2E1, suggesting the development of therapeutic strategies for patients with HFpEF.
{"title":"Soluble epoxide hydrolase deficiency rescues heart failure with preserved ejection fraction by targeting cytochrome P450 2E1","authors":"Min Zhang , Chen Chen , Xinxing Liu , Zhou Zhou , Gen Li , Xiangrui Jiang , Jingshan Shen , Hualiang Jiang , Zheng Wen , Yan Liu , Dao Wen Wang","doi":"10.1016/j.yjmcc.2025.11.005","DOIUrl":"10.1016/j.yjmcc.2025.11.005","url":null,"abstract":"<div><h3>Background</h3><div>Our prior clinical studies established a positive correlation between sEH activity and mortality in heart failure with preserved ejection fraction (HFpEF), the pathophysiological role of the sEH/EET axis in metabolic stress (obesity and metabolic syndrome) and mechanical stress (hypertension)-induced HFpEF remains unknown.</div></div><div><h3>Methods</h3><div>We elucidated the function and mechanism of sEH and EETs in ‘two-hit’ (high-fat diet and inhibition of constitutive nitric oxide synthase using Nω-nitrol-arginine methyl ester) HFpEF animal model. Langendorff system was applied to isolate cardiomyocytes from HFpEF mice. Recombinant adeno-associated virus type 9 was used to deliver cytochrome P450 2E1 (CYP2E1) to cardiac-specific knockout sEH HFpEF mice through the tail vein.</div></div><div><h3>Results</h3><div>sEH activity and expression were upregulated, while EETs levels were reduced in the hearts and isolated cardiomyocytes from HFpEF mice or cardiomyocyte cell lines pretreated with palmitate acid and Nω-nitrol-arginine methyl ester. Desuccinylation, a posttranslational modification of sEH (K)<sup>191</sup>, maintained the activity of sEH in HFpEF. Genetic or pharmacological inhibition of the sEH restored the levels of EETs and ameliorated HFpEF phenotype with significantly improved diastolic dysfunction and cardiac remodeling. Mechanically, sEH inhibitors (sEHIs) targeted CYP2E1, a crucial CYP450 enzyme, to inhibit reactive oxygen species (ROS) and fatty acid uptake. Overexpressing CYP2E1 abolished the protective effects of sEH inhibition in vivo.</div></div><div><h3>Conclusions</h3><div>These findings confirmed sEH as a therapeutic target in metabolic stress and mechanical stress-induced HFpEF mice model via the cardioprotective effects of EETs, which were mediated partially by targeting CYP2E1, suggesting the development of therapeutic strategies for patients with HFpEF.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 98-108"},"PeriodicalIF":4.7,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145540934","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 : 2025-11-12DOI: 10.1016/j.yjmcc.2025.11.001
Jie Yang , Shaopeng Cheng , Hoshun Chong , Qiuyan Zong , Yilin Wang , Tingting Tong , Yi Jiang , Jian Shi , Ronghuang Yu , Xiujuan Cai , Hanqing Luo , Hao Chen , Chuiyu Kong , Yunxing Xue , Dongjin Wang
Although cardiac fibroblast-to-myofibroblast transition (FMT) can critically exacerbate collagen deposition and adverse remodeling after myocardial infarction (MI), the underlying regulatory mechanisms remains unclear. While ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, has been implicated in cardiomyocyte ischemia injury, its role in myofibroblast transition following MI is unknown. Here, we identify cardiac fibroblasts-specific USP7 as a key mediator of FMT and fibrosis. USP7 expression was upregulated in infarcted murine hearts and isolated cardiac fibroblasts, and the upregulated expression was correlated with human fibrotic myocardium. Silencing of USP7 expression suppressed transforming growth factor (TGF)-β1-induced FMT and reduced the expression of -SMA. In comparison with the findings in USP7flox/flox mice, specific knockout of USP7 in cardiac fibroblasts and in myofibroblasts greatly attenuated fibrotic remodeling and ventricular dysfunction post-MI. Mechanistically, USP7 directly bound to Krüppel-like factor 7 (KLF7) through the N-terminal tumor necrosis factor receptor-associated factor (TRAF)-like domain, causing deubiquitination of KLF7. Cysteine at position 223 (C223) of USP7 induced K48 deubiquitination to promote KLF7 nuclear accumulation, thereby facilitating transcription of GATA3 by directly binding to the GATA3 promoter to induce the expression of pro-fibrosis genes. Adeno-associated virus 9 (AAV9)-mediated USP7 overexpression worsened systolic dysfunction and adverse remodeling. The protective effects of USP7 knockout were abolished by KLF7 overexpression. Our results indicate that USP7 contributes to FMT, thereby aggravating adverse remodeling and cardiac dysfunction by deubiquitinating KLF7 post-MI. Our findings characterize the USP7-KLF7-GATA3 axis as a novel regulator of FMT and propose fibroblast USP7 as a therapeutic target for post-MI remodeling.
{"title":"Cardiac fibroblasts-specific USP7 drives post-infarction cardiac fibrosis by deubiquitinating Krüppel-like factor 7 to promote myofibroblast activation","authors":"Jie Yang , Shaopeng Cheng , Hoshun Chong , Qiuyan Zong , Yilin Wang , Tingting Tong , Yi Jiang , Jian Shi , Ronghuang Yu , Xiujuan Cai , Hanqing Luo , Hao Chen , Chuiyu Kong , Yunxing Xue , Dongjin Wang","doi":"10.1016/j.yjmcc.2025.11.001","DOIUrl":"10.1016/j.yjmcc.2025.11.001","url":null,"abstract":"<div><div>Although cardiac fibroblast-to-myofibroblast transition (FMT) can critically exacerbate collagen deposition and adverse remodeling after myocardial infarction (MI), the underlying regulatory mechanisms remains unclear. While ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, has been implicated in cardiomyocyte ischemia injury, its role in myofibroblast transition following MI is unknown. Here, we identify cardiac fibroblasts-specific USP7 as a key mediator of FMT and fibrosis. USP7 expression was upregulated in infarcted murine hearts and isolated cardiac fibroblasts, and the upregulated expression was correlated with human fibrotic myocardium. Silencing of USP7 expression suppressed transforming growth factor (TGF)-β1-induced FMT and reduced the expression of <span><math><mi>α</mi></math></span>-SMA. In comparison with the findings in USP7<sup>flox/flox</sup> mice, specific knockout of USP7 in cardiac fibroblasts and in myofibroblasts greatly attenuated fibrotic remodeling and ventricular dysfunction post-MI. Mechanistically, USP7 directly bound to Krüppel-like factor 7 (KLF7) through the N-terminal tumor necrosis factor receptor-associated factor (TRAF)-like domain, causing deubiquitination of KLF7. Cysteine at position 223 (C223) of USP7 induced K48 deubiquitination to promote KLF7 nuclear accumulation, thereby facilitating transcription of GATA3 by directly binding to the GATA3 promoter to induce the expression of pro-fibrosis genes. Adeno-associated virus 9 (AAV9)-mediated USP7 overexpression worsened systolic dysfunction and adverse remodeling. The protective effects of USP7 knockout were abolished by KLF7 overexpression. Our results indicate that USP7 contributes to FMT, thereby aggravating adverse remodeling and cardiac dysfunction by deubiquitinating KLF7 post-MI. Our findings characterize the USP7-KLF7-GATA3 axis as a novel regulator of FMT and propose fibroblast USP7 as a therapeutic target for post-MI remodeling.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 109-126"},"PeriodicalIF":4.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523709","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 : 2025-11-11DOI: 10.1016/j.yjmcc.2025.11.003
Mandy Li, Yan Wang, Robert E. Widdop
Diabetic-related heart complications, exemplified by heart failure, represents a growing global health burden, characterised by deterioration of cardiac function, disturbances in cardiac structure such as left ventricular geometry and tissue composition. The underlying molecular mechanisms of diabetic heart failure are multifaceted, and both inflammation and oxidative stress are identified as key drivers in disease progression. Current treatments primarily focus on glycaemic control to prevent heart failure in diabetic patients, but their direct effects on the myocardium are not always clear. Upregulation of the renin-angiotensin system in the diabetic heart presents itself as a compelling therapeutic opportunity, particularly through the counter-regulatory angiotensin II type 2 receptor (AT2R) axis. AT2R activation confers cardioprotection in experimental diabetes and heart failure by attenuating pathological cardiac remodelling, including fibrosis and hypertrophy. These effects are facilitated by reductions in oxidative stress and endothelial dysfunction, enhanced nitric oxide signalling and suppression of NF-κB signalling and subsequent inflammation. This review describes the progress made to date, profiling the preclinical benefits of AT2R activation, using a suite of current and new-generation AT2R agonists in the heart, and provides evidence for the potential therapeutic use of AT2R agonists as a novel anti-fibrotic strategy, alone or in combination with standard therapy, for diabetic heart failure.
{"title":"Novel angiotensin receptor target as therapy for the diabetic heart: the AT2R","authors":"Mandy Li, Yan Wang, Robert E. Widdop","doi":"10.1016/j.yjmcc.2025.11.003","DOIUrl":"10.1016/j.yjmcc.2025.11.003","url":null,"abstract":"<div><div>Diabetic-related heart complications, exemplified by heart failure, represents a growing global health burden, characterised by deterioration of cardiac function, disturbances in cardiac structure such as left ventricular geometry and tissue composition. The underlying molecular mechanisms of diabetic heart failure are multifaceted, and both inflammation and oxidative stress are identified as key drivers in disease progression. Current treatments primarily focus on glycaemic control to prevent heart failure in diabetic patients, but their direct effects on the myocardium are not always clear. Upregulation of the renin-angiotensin system in the diabetic heart presents itself as a compelling therapeutic opportunity, particularly through the counter-regulatory angiotensin II type 2 receptor (AT<sub>2</sub>R) axis. AT<sub>2</sub>R activation confers cardioprotection in experimental diabetes and heart failure by attenuating pathological cardiac remodelling, including fibrosis and hypertrophy. These effects are facilitated by reductions in oxidative stress and endothelial dysfunction, enhanced nitric oxide signalling and suppression of NF-κB signalling and subsequent inflammation. This review describes the progress made to date, profiling the preclinical benefits of AT<sub>2</sub>R activation, using a suite of current and new-generation AT<sub>2</sub>R agonists in the heart, and provides evidence for the potential therapeutic use of AT<sub>2</sub>R agonists as a novel anti-fibrotic strategy, alone or in combination with standard therapy, for diabetic heart failure.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 83-97"},"PeriodicalIF":4.7,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513112","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}
Lower levels of Qki were reported in human and mouse-failing hearts, implicating its involvement in cardiac diseases. However, the molecular and functional effects of its downregulation in adult myocardium remain largely unknown.
Objective
We aim to uncover the effects of Qki knockdown in adult hearts.
Methods & results
Here we show that AAV9-mediated knockdown of Qki by shRNAs in the hearts of adult BALB/c mice led to cardiac malfunction, atrophy, apoptosis, heart failure, and death within two weeks. Global transcriptomic analysis of Qki knockdown hearts revealed significant dysregulation of 996 alternative splicing events upon Qki knockdown. Mechanistically, we discovered that loss of Qki promotes the exclusion of the third exon of Morf4l2, leading to higher expression of exon three excluded variant (Morf4l2Δex3). Like rodents, the RNA-seq dataset from 108 human hearts revealed a lower splice junction count of MORF4L2 exon three in hearts with low levels of QKI compared to subjects with higher QKI levels. Specific knockdown of Morf4l2Δex3 rescues Qki knockdown-induced cardiac cachexia and improves cardiac function. Moreover, Morf4l2Δex3 was increased in the colon cancer-induced cardiac cachexia mouse model, and its inhibition prevented cardiac cachexia and improved cardiac function. Mechanistically, exon three of Morf4l2 lies in the 5’UTR, and its exclusion leads to higher expression of MORF4L2 upon Qki knockdown due to the lack of a G2-quadruplex. Importantly, MORF4L2 protein sequence and localization were not affected by alternative splicing as exon three lies in the 5’UTR. We found that MORF4L2 is a chromatin-bound protein and regulates H3K27ac.
Conclusion
Qki knockdown in the adult heart leads to cardiac cachexia due to the alteration of Morf4l2 splicing. Inhibition of Morf4l2Δex3 inhibits cancer-induced cardiac cachexia, demonstrating it as a potential therapeutic target.
{"title":"The RNA-binding protein Quaking is essential for cardiac homeostasis and function by regulating Morf4l2 splicing","authors":"Sunaina Kumari , Shashi , Sandhya Singh , Abinash Swain , Shakti Prakash , Pragya Chitkara , Rakesh Kumar Sharma , Pratyush Agarwal , Samprikta Kundu , Aakash Gaur , Renu Kumari , Abhipsa Sinha , Shambhabi Chatterjee , Pankaj Prasun , Oliver Hummel , Bhaskar Pant , Kinshuk Raj Srivastava , Norbert Hübner , Dipak Datta , Kalyan Mitra , Shashi Kumar Gupta","doi":"10.1016/j.yjmcc.2025.11.002","DOIUrl":"10.1016/j.yjmcc.2025.11.002","url":null,"abstract":"<div><h3>Background</h3><div>Lower levels of <em>Qki</em> were reported in human and mouse-failing hearts, implicating its involvement in cardiac diseases. However, the molecular and functional effects of its downregulation in adult myocardium remain largely unknown.</div></div><div><h3>Objective</h3><div>We aim to uncover the effects of <em>Qki</em> knockdown in adult hearts.</div></div><div><h3>Methods & results</h3><div>Here we show that AAV9-mediated knockdown of <em>Qki</em> by shRNAs in the hearts of adult BALB/c mice led to cardiac malfunction, atrophy, apoptosis, heart failure, and death within two weeks. Global transcriptomic analysis of <em>Qki</em> knockdown hearts revealed significant dysregulation of 996 alternative splicing events upon <em>Qki</em> knockdown. Mechanistically, we discovered that loss of <em>Qki</em> promotes the exclusion of the third exon of <em>Morf4l2,</em> leading to higher expression of exon three excluded variant (<em>Morf4l2Δex3</em>). Like rodents, the RNA-seq dataset from 108 human hearts revealed a lower splice junction count of <em>MORF4L2</em> exon three in hearts with low levels of <em>QKI</em> compared to subjects with higher <em>QKI</em> levels. Specific knockdown of <em>Morf4l2Δex3</em> rescues <em>Qki</em> knockdown-induced cardiac cachexia and improves cardiac function. Moreover, <em>Morf4l2Δex3</em> was increased in the colon cancer-induced cardiac cachexia mouse model, and its inhibition prevented cardiac cachexia and improved cardiac function. Mechanistically, exon three of <em>Morf4l2</em> lies in the 5’UTR, and its exclusion leads to higher expression of MORF4L2 upon <em>Qki</em> knockdown due to the lack of a G2-quadruplex. Importantly, MORF4L2 protein sequence and localization were not affected by alternative splicing as exon three lies in the 5’UTR. We found that MORF4L2 is a chromatin-bound protein and regulates H3K27ac.</div></div><div><h3>Conclusion</h3><div><em>Qki</em> knockdown in the adult heart leads to cardiac cachexia due to the alteration of <em>Morf4l2</em> splicing. Inhibition of <em>Morf4l2Δex3</em> inhibits cancer-induced cardiac cachexia, demonstrating it as a potential therapeutic target.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 43-58"},"PeriodicalIF":4.7,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145489094","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 : 2025-11-05DOI: 10.1016/j.yjmcc.2025.10.014
David Wong , Matthew Tran , Julie Martinez , Itzetl Avila , Adrian Arrieta , Kyle Kalindjian , Elle Rathbun , Thomas M. Vondriska , Eric M. Small , Pearl Quijada
The Slit2 guidance ligand and its Roundabout (Robo) family of receptors regulate axonal guidance and vascular patterning during cardiac morphogenesis, yet the role of Slit2-Robo signaling in the adult heart remains unclear. Here, we identified epicardium-derived Slit2 as highly enriched in neonatal cardiac fibroblasts (cFBs) but markedly reduced in adult hearts. Following myocardial infarction (MI), Slit2 transiently increases in the infarct border zone seven days post-MI but declines significantly after one month. In vitro, Slit2 overexpression in cFBs selectively upregulated angiogenic genes during myofibroblast differentiation without affecting extracellular matrix (ECM) gene expression. In vivo, AAV9-mediated cardiac-specific overexpression of Slit2 (AAV9-cTNT-Slit2) improved cardiac function, increased endothelial cell (EC) proliferation and vascular density, but did not alter fibrotic deposition following MI. Conditioned media from Slit2-overexpressing cFBs promoted EC proliferation, activation, and tube forming abilities, consistent with the increased expression of pro-angiogenic Robo1 and other vascular growth factors in the myocardium of AAV9-Slit2-treated hearts. Additionally, Slit2 overexpression attenuated cardiomyocyte hypertrophy after MI and suppressed fetal gene expression in vitro. Mechanistically, Slit2 appears to mediate its cardioprotective effects through enhanced interactions with Robo1 in cFBs and ECs. These findings support Slit2-Robo signaling as a promising therapeutic target for improving blood vessel formation and maintaining cardiac muscle integrity following ischemic injury.
{"title":"Slit2-robo signaling regulates angiogenesis and repair following myocardial infarction","authors":"David Wong , Matthew Tran , Julie Martinez , Itzetl Avila , Adrian Arrieta , Kyle Kalindjian , Elle Rathbun , Thomas M. Vondriska , Eric M. Small , Pearl Quijada","doi":"10.1016/j.yjmcc.2025.10.014","DOIUrl":"10.1016/j.yjmcc.2025.10.014","url":null,"abstract":"<div><div>The Slit2 guidance ligand and its Roundabout (Robo) family of receptors regulate axonal guidance and vascular patterning during cardiac morphogenesis, yet the role of Slit2-Robo signaling in the adult heart remains unclear. Here, we identified epicardium-derived Slit2 as highly enriched in neonatal cardiac fibroblasts (cFBs) but markedly reduced in adult hearts. Following myocardial infarction (MI), Slit2 transiently increases in the infarct border zone seven days post-MI but declines significantly after one month. In vitro, Slit2 overexpression in cFBs selectively upregulated angiogenic genes during myofibroblast differentiation without affecting extracellular matrix (ECM) gene expression. In vivo, AAV9-mediated cardiac-specific overexpression of Slit2 (AAV9-cTNT-Slit2) improved cardiac function, increased endothelial cell (EC) proliferation and vascular density, but did not alter fibrotic deposition following MI. Conditioned media from Slit2-overexpressing cFBs promoted EC proliferation, activation, and tube forming abilities, consistent with the increased expression of pro-angiogenic Robo1 and other vascular growth factors in the myocardium of AAV9-Slit2-treated hearts. Additionally, Slit2 overexpression attenuated cardiomyocyte hypertrophy after MI and suppressed fetal gene expression in vitro. Mechanistically, Slit2 appears to mediate its cardioprotective effects through enhanced interactions with Robo1 in cFBs and ECs. These findings support Slit2-Robo signaling as a promising therapeutic target for improving blood vessel formation and maintaining cardiac muscle integrity following ischemic injury.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 28-42"},"PeriodicalIF":4.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471032","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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