Journal of molecular and cellular cardiology最新文献

{"title":"KCNQ2 downregulation in left stellate ganglion neurons exacerbates malignant ventricular arrhythmias after myocardial infarction","authors":"Ming-min Zhou ,&nbsp;Liao Xu ,&nbsp;Di-Zhe Huang ,&nbsp;Xi Wang ,&nbsp;Jin-qiang Peng ,&nbsp;Yu Liu","doi":"10.1016/j.yjmcc.2026.02.001","DOIUrl":"10.1016/j.yjmcc.2026.02.001","url":null,"abstract":"<div><h3>Aims</h3><div>Ventricular arrhythmias (VAs) are a leading cause of sudden cardiac death (SCD) following myocardial infarction (MI), with cardiac sympathetic hyperexcitability serving as a critical trigger. While β-blockers provide partial protection, residual arrhythmic risk persists. Neuronal M-channels (KCNQ2/3) function as critical “brakes” limiting sympathetic hyperexcitability, yet their role in post-MI ventricular arrhythmogenesis remains undefined. In this study, we investigated whether KCNQ2 downregulation in sympathetic ganglia contributes to heightened arrhythmic susceptibility following MI.</div></div><div><h3>Methods and results</h3><div>Male Sprague-Dawley rats (<em>n</em> = 104) were randomized into four groups: sham, MI, shCtrl+MI, and shKCNQ2 + MI. Adeno-associated viral vectors targeting KCNQ2 or scrambled controls were injected into the left stellate ganglion (LSG) 3 weeks before permanent left anterior descending coronary artery ligation. KCNQ2 expression was significantly reduced in LSG neurons following MI. Targeted KCNQ2 knockdown markedly exacerbated VAs burden during both acute (0-8 h) and chronic phases (4 weeks) post-MI, with increased ventricular fibrillation incidence (93% vs. 43% in shCtrl, <em>P</em> &lt; 0.05). The basal firing activity of LSG neurons was significantly greater in shKCNQ2 + MI rats compared with shCtrl+MI rats. KCNQ2 deficiency exacerbated sympatho-vagal imbalance (elevated LF/HF ratio) and increased ventricular repolarization heterogeneity. Ex vivo studies confirmed enhanced arrhythmia inducibility and reduced ventricular fibrillation threshold in the KCNQ2 knockdown group.</div></div><div><h3>Conclusion</h3><div>Knockdown of KCNQ2 in LSG neurons exacerbates cardiac sympathetic discharge activity and heightens arrhythmic vulnerability post-MI; however, the absence of direct M-current measurements and gain-of-function validation limits causal conclusions.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Pages 59-73"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137605","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 mineralocorticoid receptor: a new chapter for therapeutic regulation of diabetic cardiomyopathy","authors":"Monica Kanki ,&nbsp;Morag J. Young","doi":"10.1016/j.yjmcc.2026.01.004","DOIUrl":"10.1016/j.yjmcc.2026.01.004","url":null,"abstract":"<div><div>Diabetes mellitus is a global health burden and represents a major cause of cardiovascular disease-related morbidity and mortality. Diabetic cardiomyopathy continues to predispose individuals to overt heart failure despite significant advances in the development of anti-hyperglycaemic medications. Currently, there is a lack of biomarkers for the detection of myocardial injury in the early stages of diabetic cardiomyopathy, which underscores the urgent need to identify early disease processes and develop novel therapeutic strategies. The mineralocorticoid receptor (MR) has proven to be a valuable therapeutic target in heart failure, which may translate to a promising option to reduce the risk of cardiovascular complications in mid-to-late stages of diabetic cardiomyopathy. This narrative review discusses the role of inappropriate MR activation in common pathogenic mechanisms underlying diabetic cardiomyopathy, as well as highlighting the circadian clock as an emerging target in diabetes that has been linked to modulation of MR activation. It will also outline the cardiovascular protection yielded from anti-diabetic agents and MR antagonists (MRA) in preclinical and clinical settings of diabetes. Although our knowledge of the mechanisms of myocardial injury in diabetes is expanding quickly, current therapeutic strategies do not mitigate the high risks of cardiovascular disease in this vulnerable population. Further investment in understanding the consequences of adverse MR signalling and potentially the early introduction of MR blockade in management plans may be critical for combating the burden of cardiomyopathy in the diabetic population.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"213 ","pages":"Pages 1-13"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989709","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":"METTL3-dependent N6-methyladenosine modification on LGMN mRNA promotes macrophage ferroptosis and atherosclerosis","authors":"Yang He ,&nbsp;Kaisheng Jiang ,&nbsp;Junhong Sun ,&nbsp;Qianhao Zhao ,&nbsp;Jiacheng Yue ,&nbsp;Wenzhao Wei ,&nbsp;Jie Cao ,&nbsp;Da Zheng ,&nbsp;Hui Yao ,&nbsp;Shuquan Zhao ,&nbsp;Hu Zhao ,&nbsp;Erwen Huang","doi":"10.1016/j.yjmcc.2026.01.003","DOIUrl":"10.1016/j.yjmcc.2026.01.003","url":null,"abstract":"<div><div>N6-methyladenosine (m6A) modification plays important roles in various biological processes, yet its function in macrophages and its potential link to ferroptosis in promoting atherosclerosis (AS) remain unclear. In this study, elevated levels of m6A modification and methyltransferase-like 3 (METTL3) expression were observed in AS arteries of mice. The number of METTL3-positive macrophages increased in both mouse and human AS arteries. Systemic inhibition or macrophage-specific knockdown of METTL3 attenuated AS plaque formation in mice. RNA-sequencing revealed that ferroptosis-associated genes were enriched following METTL3 knockdown in bone marrow-derived macrophages (BMDM). Consistent with this, inhibition of ferroptosis also reduced AS plaques. Further analysis showed increased m6A modification and expression of legumain (LGMN) in mouse AS arteries. Elevated LGMN expression was also detected in oxidized low-density lipoprotein (ox-LDL)-treated BMDM and in macrophages within AS lesions. Knockdown of LGMN in BMDM attenuated ox-LDL-induced ferroptosis, lipid deposition, and inflammatory responses. Macrophage-specific knockdown of LGMN in mice reduced plaque formation and ferroptosis in AS arteries. Additionally, macrophage-specific METTL3 knockdown suppressed the upregulation of LGMN expression in AS arteries. The effects of ox-LDL on BMDM were abolished by METTL3 knockdown but rescued by LGMN overexpression. Mechanistically, YTHDF1 bound to m6A-methylated LGMN mRNA and enhanced its translation. Together, The in vivo and in vitro results demonstrate that LGMN acts as a novel mediator of AS by linking METTL3-dependent m6A modification to macrophage ferroptosis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 89-103"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145933712","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":"Watching the clock: Blood pressure and cardiovascular disease influence circadian machinery in pre-clinical models","authors":"Sophia A. Eikenberry,&nbsp;Michelle L. Gumz","doi":"10.1016/j.yjmcc.2025.12.010","DOIUrl":"10.1016/j.yjmcc.2025.12.010","url":null,"abstract":"<div><div>Circadian rhythms drive cardiovascular health, and when dysfunctional, disease. Circadian biology rules daily rhythms in physiological mechanisms which allow our bodies to coordinate function with the demands of the external environment. However, the machinery underlying circadian rhythms, termed the “molecular clock”, can become altered by both external and internal factors. For instance, breaking the clock through disrupted light exposure can drive high blood pressure, which is detrimental to cardiovascular health. Importantly, cardiovascular disease itself can disrupt the molecular clock, further exacerbating pathology. The focus of this review is this latter aspect of the bi-directional relationship between circadian machinery and cardiovascular function, investigated in preclinical models. First, we describe the importance of blood pressure regulation and relevant systems. We then describe the existence of circadian rhythms in blood pressure, and briefly, how a broken clock can disrupt these rhythms and lead to disease. The focus of this review will be to outline evidence from pre-clinical and translational studies investigating the direct impact of cardiovascular disease on circadian machinery in the brain, heart, aorta, and kidney. This is with the goal of 1) highlighting the potential for harnessing the molecular clock through circadian interventions in combination with other treatment, and 2) aiding pre-clinical cardiovascular researchers in understanding their results which may be impacted by time of day.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 51-59"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900581","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":"Transcription initiation factor-1A regulates the contraction of vascular smooth muscle and maintains blood pressure","authors":"Xiaolin Yue ,&nbsp;Yawei Wang ,&nbsp;Zhinan Wu ,&nbsp;Hanlin Lu ,&nbsp;Fan Jiang ,&nbsp;Wencheng Zhang ,&nbsp;Yan Liu","doi":"10.1016/j.yjmcc.2026.01.002","DOIUrl":"10.1016/j.yjmcc.2026.01.002","url":null,"abstract":"<div><div>Hypertension is a complex condition influenced by many factors. RNA polymerase I (pol I)-specific transcription initiation factor-1A (TIF-1A) regulates ribosome biosynthesis by participating in the formation of a competent pre-initiation complex. However, limited information is available regarding the role of TIF-1A in vascular smooth muscle cells (VSMCs) and its impact on blood pressure. This study investigated the biological function of TIF-1A in the modulation of smooth muscle contraction and explored the potential therapeutic targets of hypertension. Vascular smooth muscle-specific <em>Tif-1a</em>-knockout (<em>Tif-1a</em>^SMKO) mice were generated by crossbreeding <em>Tif-1a</em>^flox/flox and SMMHC-CreER^T2 mice. The angiotensin II (Ang II)-infused mice and spontaneously hypertensive rats were used as animal models of hypertension. The primary mouse smooth muscle cell model induced by Ang II was used for <em>in vitro</em> observations. Compared to that of the control, the phenotype of the <em>Tif-1a</em>^SMKO mice exhibited lower blood pressure. The contractile response to vasoconstrictors was also lower in mesenteric artery segments isolated from <em>Tif-1a</em>^SMKO mice. Functional abnormalities in <em>Tif-1a</em>^SMKO mice have been attributed to ribosomal dysfunction, which results in decreased ribosomal biosynthesis. Consistently, the expression of proteins associated with smooth muscle contraction decreased in <em>Tif-1a</em>-deficient smooth muscle cells. Finally, the smooth muscle-specific deletion of <em>Tif-1a</em> attenuated Angiotensin II-induced hypertension and vascular remodeling in mice. Administration of RNA pol I transcription inhibitor BMH-21 ameliorates hypertension in spontaneously hypertensive rats. TIF-1A regulated vascular smooth muscle contraction and maintained blood pressure by modulating ribosomal biosynthesis. Thus, TIF-1A inhibition may represent a new research orientation for the treatment of hypertension.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 38-50"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917693","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":"Phenotypes and mechanisms of dysfunctional cardiac T-lymphocytes in dilated cardiomyopathy patients","authors":"Austin Angelotti ,&nbsp;Thiruvelselvan Ponnusamy ,&nbsp;Vinay Kumar ,&nbsp;Gianna V. Passarelli ,&nbsp;Jozef Malysz ,&nbsp;Balakrishnan Mahesh ,&nbsp;Behzad Soleimani ,&nbsp;Elisa A. Bradley ,&nbsp;Shyam S. Bansal","doi":"10.1016/j.yjmcc.2025.12.011","DOIUrl":"10.1016/j.yjmcc.2025.12.011","url":null,"abstract":"<div><h3>Background</h3><div>Dilated cardiomyopathy (DCM) is characterized by increased infiltration and activation of the innate immune system, including neutrophils, monocytes/macrophages, and dendritic cells. However, the phenotypic profile of cardiac CD3⁺ T-cells and its CD4⁺ and CD8⁺ subsets have not been characterized in DCM patients.</div></div><div><h3>Methods</h3><div>We studied phenotypic signatures of T-cell subsets by analyzing publicly available single-cell and single-nuclear transcriptomic datasets from control and failing hearts of DCM patients.</div></div><div><h3>Results</h3><div>Our analysis revealed increased cardiac infiltration of CD3⁺ T-cells in DCM patients with transcriptomic signatures indicating antigenic activation, T-cell exhaustion, diminished oxidative phosphorylation, and elevated TNF/NFκB and profibrotic TGF signaling. Among T-cell subsets, both CD4⁺ and CD8⁺ T-cells were found to be highly proliferative (increased G2M) and activated. Transcription profiling demonstrated four phenotypically different subsets for both CD8⁺ and CD4⁺ T-cells, however, only CD4⁺ T-cell subsets, regulatory T-cells and tissue resident memory (TRM) CD4⁺ T-cells, were significantly increased. Importantly, TRM cells displayed decreased expression of classical egress markers, such as CCR7, SELL, and MAL, and increased pro-inflammatory and pro-fibrotic signaling. We also observed increased estrogen receptor (ER)α expressing (with amplified ERα signaling) cardiac CD4⁺ T-cells which directly correlated with systolic dysfunction and mediated their pro-fibrotic effects in DCM patients.</div></div><div><h3>Conclusion</h3><div>Here we demonstrate for the first time, an “activated phenotype” with increased pro-inflammatory and profibrotic signaling in cardiac CD3⁺ T-cells and its CD4⁺ helper T-cell subset in DCM hearts. Notably, increased ERα signaling provide novel avenues for targeted immunomodulatory therapies to modify DCM progression.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 16-25"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843987","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":"AAV-TNNI3 rescues an experimental murine Tnni3 mutation resulting in thin filament mediated DCM","authors":"Paul J. Bushway ,&nbsp;Wei Feng ,&nbsp;Marina Sampaio De Menezes Cruz ,&nbsp;Sofie Maisel ,&nbsp;Aysen Shathaya ,&nbsp;Pranita Rao ,&nbsp;Umang Patel ,&nbsp;Jinsun Park ,&nbsp;Chao Chen ,&nbsp;Zhiyuan Tang ,&nbsp;Betul Gunes ,&nbsp;Eren Gunes ,&nbsp;Mao Ye ,&nbsp;Yusu Gu ,&nbsp;Eric Adler","doi":"10.1016/j.yjmcc.2026.01.001","DOIUrl":"10.1016/j.yjmcc.2026.01.001","url":null,"abstract":"<div><div>Cardiac thin filament mutations in <em>TNNI3</em> are associated with up to 3 % of hypertrophic (HCM) cardiomyopathy cases and contribute to severe restrictive (RCM) and dilated (DCM) cardiomyopathy caseloads. As such, thin filament cardiomyopathy mediated by <em>TNNI3</em> mutations is an orphan disease with unmet therapeutic need. Gene therapy is one approach to addressing orphan disease but has been restricted to the repletion of protein deficiency. Based on the best available knowledge, <em>TNNI3</em> gene therapy has never been applied in the context of a functional mutant protein. Described here is the viral gene therapy rescue at a 4-month endpoint of an experimental murine <em>Tnni3</em> mutation resulting in slow-onset dilated cardiomyopathy (DCM) with cardiac failure at 12–18 months. Mutant mice treated with AAV encoding wild-type (WT) human <em>TNNI3</em> at 1.0E+14 vg/kG prevented the onset of DCM pathology. This work describes the first adeno-associated virus (AAV) gene therapy replacement of functional mutated Tnni3 protein. The results suggest a broader application of gene therapy for gene replacement.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 26-37"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911869","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":"JTC801 inhibited CA9 activation via HIF-1α to promotes alkaliptosis in vascular smooth muscle cells and alleviate the formation of aortic dissection","authors":"Yang Zhou ,&nbsp;Xiao-Ping Xie ,&nbsp;Bo-Lai Shen ,&nbsp;Ao Wang ,&nbsp;Bo-Wen Li ,&nbsp;Zhi-Wei Wang","doi":"10.1016/j.yjmcc.2025.12.005","DOIUrl":"10.1016/j.yjmcc.2025.12.005","url":null,"abstract":"<div><h3>Background</h3><div>Aortic dissection (AD) is a life-threatening cardiovascular condition characterized by high morbidity and mortality rates. However, the molecular mechanism of intracellular pH in AD development has not been fully elucidated. In this study, the role of carbonic anhydrase 9 (CA9) in VSMCs intracellular pH and the regulatory mechanism were investigated.</div></div><div><h3>Methods</h3><div>Cell viability was examined by cell counting kit-8 (CCK-8) and intracellular pH was detected by BCECF-AM probe. The regulation of CA9 transcription by HIF-1α was measured by Cut &amp;run-qPCR assay. The levels of CA9, HIF-1α, MMP2 and α-SMA were evaluated by RT-qPCR, Western blot and Immunofluorescence.</div></div><div><h3>Results</h3><div>Our results demonstrated that CA9 was significantly upregulated in AD tissues, primarily localized in VSMCs, and associated with increased MMP2 levels, while α-SMA levels decreased. Silencing CA9 in VSMCs resulted in reduced cell viability and increased intracellular pH. Additionally, we found that HIF-1α was upregulated in AD, regulating CA9 expression in VSMCs. Treatment with JTC801 in a BAPN-induced mouse model reduced CA9 and HIF-1α expression, improving survival and decreasing AD incidence.</div></div><div><h3>Conclusion</h3><div>This study establishes CA9 as a hypoxia-responsive mediator of pH dysregulation in AD, modulated by HIF-1α. Targeting the HIF-1α/CA9 axis with JTC801 presents a novel therapeutic strategy to restore VSMC homeostasis and ECM integrity. These findings advance our understanding of intracellular pH in AD and highlight this approach may be a potential therapeutic target.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 75-88"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804880","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":"Pseudo-acetylation of ACTC1 K326 and K328 promotes dysinhibition of reconstituted human cardiac thin filaments","authors":"Kripa Chitre ,&nbsp;Olga E. Karpicheva ,&nbsp;Chloe J. King ,&nbsp;Michael J. Rynkiewicz ,&nbsp;Axel J. Fenwick ,&nbsp;John F. Dawson ,&nbsp;D. Brian Foster ,&nbsp;William Lehman ,&nbsp;Anthony Cammarato","doi":"10.1016/j.yjmcc.2025.12.008","DOIUrl":"10.1016/j.yjmcc.2025.12.008","url":null,"abstract":"<div><div>Electrostatic interactions between actin residues K326 and K328 and tropomyosin bias tropomyosin to an F-actin location where it blocks myosin attachment. K326/328 acetylation neutralizes their charge, potentially disrupting thin filament-based contractile regulation. We verified acetylation of K326/328 on human cardiac actin (ACTC1) and generated recombinant K326/328Q, pseudo-acetylated ACTC1. Pseudo-acetylation reduced inhibition of myosin-driven motility of F-actin-tropomyosin and F-actin-tropomyosin-troponin at low Ca²⁺. Cryo-EM-based and computational modeling revealed that pseudo-acetylation did not alter tropomyosin positioning along F-actin but decreased local F-actin-tropomyosin interaction energy. Thus, by reducing the energetic demands required for myosin to displace tropomyosin, ACTC1 K326/328 acetylation may promote contractile activation.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 10-15"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827921","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":"Atrial t-tubules adopt a distinct developmental state as Ca2+ handling matures postnatally","authors":"C.E.R. Smith,&nbsp;C.J. Quinn,&nbsp;J.D. Clarke,&nbsp;Z. Sultan,&nbsp;H. Najem,&nbsp;N.C. Denham,&nbsp;D.C. Hutchings,&nbsp;A.S. Whitley,&nbsp;G.W.P. Madders,&nbsp;J.L. Caldwell,&nbsp;L.K. Toms,&nbsp;D.A. Eisner,&nbsp;C. Pinali,&nbsp;A.W. Trafford,&nbsp;K.M. Dibb","doi":"10.1016/j.yjmcc.2025.12.012","DOIUrl":"10.1016/j.yjmcc.2025.12.012","url":null,"abstract":"<div><div>Transverse (t)-tubules ensure a uniform rise in cellular Ca²⁺ facilitating cardiac contraction. They play a key role in the large mammalian atria (including human) and their loss in heart failure is associated with impaired Ca²⁺ release. While t-tubule restoration is therefore an ideal therapeutic target, atrial t-tubule development is not well understood. Here we sought to determine how atrial t-tubules develop and the impact on Ca²⁺ handling. Atrial postnatal development was examined in sheep from newborn through to adulthood. T-tubule development was assessed using confocal microscopy and serial block face Scanning Electron Microscopy. Voltage clamp coupled with Ca²⁺ epifluorescence was used to assess concomitant functional changes to Ca²⁺ handling. Atrial t-tubule density increased until 3 months of age when the t-tubule network was disordered. As development continued t-tubules became more ordered but surprisingly the distance of the cell interior to t-tubule membrane increased due to a lack of additional t-tubules coupled with increased cell width. As t-tubules developed, L-type Ca²⁺ current density (<em>I</em>_Ca-L) and sarcoplasmic reticulum (SR) Ca²⁺ content decreased. Although these changes would be expected to decrease Ca²⁺ transient amplitude, Ca²⁺ buffering was simultaneously reduced which our data suggests maintains Ca²⁺ transient amplitude during neonatal development. By understanding how the Ca²⁺ transient is preserved despite drastic changes in t-tubule density and structure during development, this study may provide insights into adaptive mechanisms in Ca²⁺ cycling that mitigate the impact of reduced t-tubule density.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"212 ","pages":"Pages 60-74"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911832","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}