Journal of molecular and cellular cardiology最新文献

{"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 ,&nbsp;Nicolae Moise ,&nbsp;Mario J. Mendez ,&nbsp;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":"2026-02-01","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}

{"title":"Extracellular-cAMP suppresses pulmonary arterial hypertension-induced ventricular arrhythmias","authors":"Marine Cacheux ,&nbsp;Benjamin Strauss ,&nbsp;Shestruma Parajuli ,&nbsp;Aymen Halouani ,&nbsp;Michael G. Katz ,&nbsp;Seun Imani ,&nbsp;Samar Antar ,&nbsp;Nestor Bedoya ,&nbsp;Lahouaria Hadri ,&nbsp;Fadi G. Akar ,&nbsp;Yassine Sassi","doi":"10.1016/j.yjmcc.2025.12.004","DOIUrl":"10.1016/j.yjmcc.2025.12.004","url":null,"abstract":"<div><div>Pulmonary Arterial Hypertension (PAH), a major cause of right ventricular failure, is associated with a high 5-year mortality rate. Arrhythmias account for a significant proportion of morbidity and mortality in PAH patients. Hence, there is a critical need for new therapies to effectively treat PAH-related cardiac arrhythmias. The purpose of this study was to evaluate the efficacy of extracellular cyclic adenosine monophosphate (e-cAMP) treatment in reversing pathophysiological electrophysiological (EP) remodeling and arrhythmia propensity caused by PAH. Ex-vivo optical action potential (AP) mapping, real-time reverse transcription–polymerase chain reaction, immunostaining, morphological and histologic analyses were performed on two different models of pulmonary hypertension (Monocrotaline and Sugen/pneumonectomy) to test the impact of e-cAMP treatment in suppressing ventricular arrhythmias in PAH. PAH diseased rats from both models exhibited a high propensity of inducible ventricular tachycardia (VT). Remarkably, e-cAMP treatment suppressed the incidence of VT in both models. Examination of the EP substrate revealed action potential duration prolongation and marked conduction slowing in PAH-diseased animals. These features, however, were significantly reversed by e-cAMP treatment. Moreover, e-cAMP reversed the development of AP alternans in PAH. Extracellular cAMP-treated rats exhibited a significant decrease in myocardial fibrosis and hypertrophic remodeling. Reversal of EP remodeling by e-cAMP was accompanied by decreased pulmonary vascular remodeling and by restored cardiac expression of key ion channel transcripts. Extracellular cAMP treatment reduces the incidence of ventricular arrhythmias and suppresses pathological EP remodeling by restoring cardiac and pulmonary vascular remodeling. This approach may represent a new therapeutic modality for arrhythmia suppression in PAH patients.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 109-118"},"PeriodicalIF":4.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145723899","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}

{"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 ,&nbsp;Yuru Cao ,&nbsp;Xianle Liu ,&nbsp;Qing Yang ,&nbsp;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 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.</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 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.</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":"2026-02-01","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}

{"title":"Inhibition of Pyk2 prevents Cx43 remodeling and cardiomyocyte injury during hypoxic and adrenergic stress","authors":"Ming Ding ,&nbsp;Li Zheng ,&nbsp;Tapan A. Patel ,&nbsp;Matthew C. Zimmerman ,&nbsp;Kaushik P. Patel ,&nbsp;Paul L. Sorgen","doi":"10.1016/j.yjmcc.2025.12.006","DOIUrl":"10.1016/j.yjmcc.2025.12.006","url":null,"abstract":"<div><div>Hypoxia induces pathological remodeling in cardiomyocytes, in part by disrupting gap junction communication through Connexin43 (Cx43) phosphorylation and internalization. Here, we identify Proline-rich tyrosine kinase 2 (Pyk2) as a critical mediator of hypoxia- and adrenergic-induced Cx43 remodeling and cardiomyocyte dysfunction. Neonatal rat ventricular myocytes exposed to hypoxia (1 % O₂) for 1 or 24 h exhibited increased expression of hypoxia-inducible factor 1α and activated Pyk2 (pY402 and pY579/580), without changes in the total level of Pyk2. Hypoxia also enhanced Cx43 phosphorylation at Y265, a Pyk2-specific site, and increased expression of GJA1–20 k, an alternatively translated Cx43 isoform that supports Cx43 trafficking and mitochondrial function. Pharmacological Pyk2 inhibition with PF4618433 prevented hypoxia-induced Pyk2 activation, Cx43 phosphorylation, and attenuated the increase in GJA1–20 k expression. Immunofluorescence analysis revealed that hypoxia reduced Cx43 localization at intercellular junctions, an effect reversed by PF4618433 treatment. Functionally, Pyk2 inhibition reduced cell damage, as reflected by lower lactate dehydrogenase release and improved contractile activity. Mechanistically, PF4618433 attenuated apoptosis, oxidative stress, and preserved mitochondrial membrane potential, consistent with improved mitochondrial function. Furthermore, norepinephrine-induced Pyk2 activation and Cx43 Y265 phosphorylation were comparably suppressed by PF4618433, linking Pyk2 to both hypoxic as well as adrenergic stress signaling in cardiomyocytes. These findings demonstrate that Pyk2 activation promotes Cx43 downregulation, contributing to cardiomyocyte injury under hypoxic and adrenergic stress. Inhibition of Pyk2 preserves gap junction integrity, maintains mitochondrial function, and enhances cell survival, supporting Pyk2 as a promising therapeutic target in cardiac injury.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"211 ","pages":"Pages 119-130"},"PeriodicalIF":4.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786581","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}

{"title":"Single cell transcriptomic landscape of adult and pediatric non-ischemic cardiomyopathy","authors":"Hanna J. Tadros ,&nbsp;Diwakar Turaga ,&nbsp;Kyle Hope ,&nbsp;Joseph A. Spinner ,&nbsp;Iki Adachi ,&nbsp;Xiao Li ,&nbsp;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":"2026-02-01","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}

{"title":"The influence of lactation on postpartum murine heart growth","authors":"Molly S. Kaissar ,&nbsp;Elnaz Ghajar-Rahimi ,&nbsp;Adalyn Meeks ,&nbsp;Arden Shen ,&nbsp;Yusheng Wu ,&nbsp;Craig J. Goergen ,&nbsp;Kyoko Yoshida","doi":"10.1016/j.yjmcc.2025.10.012","DOIUrl":"10.1016/j.yjmcc.2025.10.012","url":null,"abstract":"<div><div>The cardiovascular system adapts to meet rising physiological demands throughout pregnancy. Notably, the left ventricle grows to support this increased workload, which is thought to reverse after delivery. Yet, whether the heart returns to its pre-pregnant size, shape, and function postpartum is unclear. This postpartum cardiac recovery has been historically studied in rodents. However, despite previous research showing that postpartum-specific conditions like lactation affect hemodynamics and heart weight, the relationship between these hemodynamic changes and cardiac growth remains unclear. In this study, we investigate the impact of lactation on postpartum cardiac recovery. We monitored changes in left ventricular mass, volume, and function throughout pregnancy and postpartum in mice using 4D cardiac ultrasound in animals allowed to nurse their pups for 21 days postpartum and in those whose pups were removed immediately after delivery. We analyzed the relationship between the observed hemodynamics and heart growth in these mice using an existing multiscale computational model of heart growth. Here, we observe that pregnancy-induced cardiac hypertrophy reverses by one week postpartum in non-lactating mice but continues increasing after delivery in lactating mice. Our computational analysis suggests that hemodynamic and biological factors have distinct but complementary roles in driving postpartum growth. Further, our animal-specific simulations indicate that individual hemodynamic changes contribute to the observed variability in experimental heart growth, particularly throughout lactation. Overall, this study provides a detailed timeline of cardiac hypertrophy during and after pregnancy, emphasizes the significance of lactation status on postpartum recovery, and highlights the importance of hemodynamics to this phenomenon.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 1-11"},"PeriodicalIF":4.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431690","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}

{"title":"Spatiotemporal determinants of stretch-activated channel-induced re-entry in ventricular tissue: An in-silico study","authors":"Melania Buonocunto ,&nbsp;Tammo Delhaas ,&nbsp;Aurore Lyon ,&nbsp;Jordi Heijman ,&nbsp;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":"2026-01-01","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}

{"title":"Novel angiotensin receptor target as therapy for the diabetic heart: the AT2R","authors":"Mandy Li,&nbsp;Yan Wang,&nbsp;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 (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.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 83-97"},"PeriodicalIF":4.7,"publicationDate":"2026-01-01","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}

{"title":"Homocysteine activates endothelial TP receptor to promote von Willebrand factor secretion and thrombosis","authors":"Jiachen Zhang ,&nbsp;Xinyu Jia ,&nbsp;Ping Zhu ,&nbsp;Mengzheng Zhao ,&nbsp;Haodong Du ,&nbsp;Xinyi Yu ,&nbsp;Jing Huang ,&nbsp;Yegong Xie ,&nbsp;Yequn Chen ,&nbsp;Yi Zhu ,&nbsp;Qiankun Bao ,&nbsp;Jinlong He ,&nbsp;Liu Yao","doi":"10.1016/j.yjmcc.2025.10.013","DOIUrl":"10.1016/j.yjmcc.2025.10.013","url":null,"abstract":"<div><div>Hyperhomocysteinemia (HHcy), characterized by elevated plasma homocysteine (Hcy) levels, is a recognized risk factor for thrombosis and an independent contributor to acute coronary syndrome, although its underlying mechanisms are not fully understood. The current study is to investigate the impact of HHcy on arterial thrombosis and the underlying mechanisms. In this study, we established an HHcy mouse model using a high-methionine diet and found that HHcy significantly accelerated thrombosis. We identified that Hcy enhanced von Willebrand factor (vWF) secretion from endothelial cells, leading to increased FVIII-vWF binding and platelet adhesion. Moreover, we observed a significant positive correlation between vWF and Hcy levels in the plasma of 150 patients with acute coronary syndrome. Mechanistically, GPCR screening revealed that Hcy-induced increase in vWF levels was mediated by activating the thromboxane prostanoid receptor (TPr) on endothelial cells. Hcy might function as an endogenous ligand binding to TPr and subsequently activated the Gαq-PLC-Ca²⁺ pathway to promote vWF secretion. Pharmacological inhibition or endothelial-specific deletion of TPr effectively reduced plasma vWF levels and protected against HHcy-related thrombosis. Our findings underscored the pivotal role of TPr in mediating Hcy-induced procoagulant states and suggested that targeting the TPr signaling pathway could be a promising therapeutic strategy for treating HHcy-related thrombosis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 59-71"},"PeriodicalIF":4.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145438335","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}

{"title":"The RNA-binding protein Quaking is essential for cardiac homeostasis and function by regulating Morf4l2 splicing","authors":"Sunaina Kumari ,&nbsp;Shashi ,&nbsp;Sandhya Singh ,&nbsp;Abinash Swain ,&nbsp;Shakti Prakash ,&nbsp;Pragya Chitkara ,&nbsp;Rakesh Kumar Sharma ,&nbsp;Pratyush Agarwal ,&nbsp;Samprikta Kundu ,&nbsp;Aakash Gaur ,&nbsp;Renu Kumari ,&nbsp;Abhipsa Sinha ,&nbsp;Shambhabi Chatterjee ,&nbsp;Pankaj Prasun ,&nbsp;Oliver Hummel ,&nbsp;Bhaskar Pant ,&nbsp;Kinshuk Raj Srivastava ,&nbsp;Norbert Hübner ,&nbsp;Dipak Datta ,&nbsp;Kalyan Mitra ,&nbsp;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 &amp; 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":"2026-01-01","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}