Journal of molecular and cellular cardiology最新文献

{"title":"Compromised repolarization reserve in a murine model of catecholaminergic polymorphic ventricular tachycardia caused by RyR2-R420Q mutation","authors":"Spyros Zissimopoulos ,&nbsp;Pavel Kirilenko ,&nbsp;Aitana Braza-Boïls ,&nbsp;Esther Zorio ,&nbsp;Yueyi Wang ,&nbsp;Ana Maria Gomez ,&nbsp;Mark B. Cannell ,&nbsp;Branko Latinkic ,&nbsp;Ewan D. Fowler","doi":"10.1016/j.yjmcc.2025.07.014","DOIUrl":"10.1016/j.yjmcc.2025.07.014","url":null,"abstract":"<div><h3>Background</h3><div>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited heart disease characterised by stress-induced arrhythmias that are thought to be caused by delayed afterdepolarizations resulting from abnormal Ca²⁺ cycling. Some patients exhibit unusually large ECG U-waves that could be associated with altered ventricular repolarization, but the possible link with dysfunctional RyR2 is unclear. We investigated whether increased Ca²⁺ leak during systole disrupts repolarization in a transgenic mouse model of CPVT.</div></div><div><h3>Methods</h3><div>Electrocardiograms were recorded in patients with RyR2-R420Q CPVT mutation (R420Q). Experiments were performed on control and R420Q knock-in mouse hearts and ventricular myocytes.</div></div><div><h3>Results</h3><div>R420Q patients had larger resting U-waves than family member controls. R420Q mouse hearts exhibited greater prolongation of monophasic APs following pauses in pacing and during beta-adrenergic stimulation. Ventricular ectopic beats during repolarization were more prevalent in R420Q mouse hearts following pacing-pauses and during premature electrical stimulation. Early afterdepolarizations (EADs) occurred in isolated R420Q myocytes during beta-adrenergic stimulation and coincided with increased Ca²⁺ leak during the Ca²⁺ transient decay, in the form of late Ca²⁺ sparks (LCS). AP voltage clamp electrophysiology experiments, analysis of LCS recovery, and computer simulations of hyperactive RyR2 supported a mechanism involving increased RyR2 sensitivity and/or reduced refractoriness that increased LCS frequency and inward sodium/calcium exchange current, resulting in AP prolongation and EADs.</div></div><div><h3>Conclusions</h3><div>Ca²⁺-mediated AP lengthening and EADs may contribute to proarrhythmic behaviour in CPVT caused by gain-of-function R420Q mutation. Loss of repolarization reserve is not specifically targeted by CPVT therapies but could be an opportunity for therapeutic intervention.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 127-140"},"PeriodicalIF":4.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717966","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":"Targeting endothelial SMAD4 ameliorates endothelial dysfunction in hypertensive mice","authors":"Jinzhao Yang ,&nbsp;Jiang-Yun Luo ,&nbsp;Hongyin Chen ,&nbsp;Wai San Cheang ,&nbsp;Juan Huang ,&nbsp;Li Wang ,&nbsp;Wing Tak Wong ,&nbsp;Litao Sun ,&nbsp;Yu Huang ,&nbsp;Xiao Yu Tian ,&nbsp;Yang Zhang","doi":"10.1016/j.yjmcc.2025.07.011","DOIUrl":"10.1016/j.yjmcc.2025.07.011","url":null,"abstract":"<div><h3>Objective</h3><div>Endothelial dysfunction is a key contributor to hypertension, and dysregulation of TGF-β/BMP signaling pathways exacerbates vascular pathogenesis. However, the precise role of SMAD4 in the development of vascular inflammation and dysfunction in hypertension remains poorly understood.</div></div><div><h3>Methods</h3><div>Tie2-Cre/ERT2 system was used to generate an endothelial-specific Smad4 knockout mouse. Hypertension was induced by infusion of angiotensin II (Ang II) via implanting an osmotic pump subcutaneously. Endothelium-dependent relaxations (EDRs) of various blood vessels were assessed using a wire myograph system. Gene expression in vivo and in vitro was evaluated through RNA-seq, qPCR, immunofluorescence staining, and western blotting. Nitric oxide (NO) and reactive oxygen species (ROS) production were measured using fluorescent probes under confocal microscopy.</div></div><div><h3>Results</h3><div>EC-Smad4 KO mice showed a significant reduction in Ang II-induced blood pressure elevation compared to control EC-Smad4 WT mice. EDRs in the aorta, mesenteric, and carotid arteries were markedly improved in EC-Smad4 KO mice. In the aortic endothelium, excess ROS generation and VCAM1 expression induced by Ang II were suppressed in EC-Smad4 KO mice. SMAD4 knockdown also led to diminished phosphorylation of p38 MAPK in response to Ang II, increased phosphorylated eNOS (p-eNOS) at Ser1177. Additionally, Smad4 downregulation resulted in reduced mRNA and protein levels of GRP78, ATF6, and PERK, key markers of tunicamycin-induced endoplasmic reticulum (ER) stress.</div></div><div><h3>Conclusion</h3><div>Smad4 signaling is a critical mediator of endothelial dysfunction and vascular inflammation in hypertension. Endothelial-specific deletion of Smad4 ameliorates vascular dysfunction by reducing oxidative stress, suppressing ER stress, and alleviating vascular inflammation.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 44-53"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637275","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":"Enhancement of sodium current contributes to the maintenance of conduction velocity in the aging myocardium","authors":"E.V. Minnebaeva ,&nbsp;M.A. Gonotkov ,&nbsp;A.V. Durkina ,&nbsp;E.A. Lebedeva ,&nbsp;A.V. Fedorov ,&nbsp;M.A. Chelombitko ,&nbsp;O.B. Pustovit ,&nbsp;T.S. Filatova ,&nbsp;J.E. Azarov ,&nbsp;O.G. Bernikova","doi":"10.1016/j.yjmcc.2025.07.013","DOIUrl":"10.1016/j.yjmcc.2025.07.013","url":null,"abstract":"<div><h3>Introduction</h3><div>The aging myocardium undergoes significant electrophysiological and structural remodeling. These complex alterations may affect conduction velocity (CV), whose age-related changes remain unclear. This study aims at evaluation of the CV changes in the rats of different ages and assessment of the contribution of cellular and tissue factors into CV.</div></div><div><h3>Methods</h3><div>The CV was determined in 3-, 12- and 24-month-old anesthetized rats using epicardial mapping under ventricular stimulation. The contribution of gap junction functionality to CV was assessed using carbenoxolone, an uncoupling agent for Cx43. The measurement of sodium ion current (I_Na) was performed in isolated ventricular cardiomyocytes using the patch-clamp technique. Expression of gene transcripts encoding Cx43 (GJA1a) and sodium currents (SCN5a) were assessed using RT-PCR analysis.</div></div><div><h3>Results</h3><div>The baseline longitudinal conduction velocity (CV_L) did not differ between 3-, 12- and 24-month-old groups. Intravenous administration of carbenoxolone decreased the CV_L only in the 3-month-old animals. The density of sodium current (I_Na) of 24-month-old rats was greater as compared to 3-month-old rats. The extent of fibrosis was less prominent in 3-month-old rats than in the older animals. The expression of SCN5a gene transcripts was increased and expression of GJA1a was decreased in the 24-month-old rats.</div></div><div><h3>Conclusions</h3><div>The enhancement of sodium current preserves conduction velocity despite impaired connexin function and increased fibrosis in the aging myocardium.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 102-112"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667765","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":"Corrigendum to “Detection of regular rotational activity during cardiac arrhythmia using the Helmholtz decomposition for directed graphs.” [Journal of Molecular and Cellular Cardiology 204 (2025) p40–54]","authors":"Sebastiaan Lootens ,&nbsp;Robin Van Den Abeele ,&nbsp;Vineesh Kappadan ,&nbsp;Balvinder Handa ,&nbsp;Matthias Duytschaever ,&nbsp;Sebastien Knecht ,&nbsp;Armin Luik ,&nbsp;Annika Haas ,&nbsp;Eike M. Wülfers ,&nbsp;Arthur Santos Bezerra ,&nbsp;Bjorn Verstraeten ,&nbsp;Sander Hendrickx ,&nbsp;Arstanbek Okenov ,&nbsp;Timur Nezlobinsky ,&nbsp;Fu Siong Ng ,&nbsp;Nele Vandersickel","doi":"10.1016/j.yjmcc.2025.07.001","DOIUrl":"10.1016/j.yjmcc.2025.07.001","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Page 113"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703846","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":"LncRNA 91234.1 targets PRMT1/ASCL4/GPX4 axis to regulate formaldehyde-induced cardiomyocyte ferroptosis and congenital heart disease","authors":"Sijia Zhao ,&nbsp;Pin Sun ,&nbsp;Chao Wang ,&nbsp;Xiaolu Li ,&nbsp;Zhenyang Xiu ,&nbsp;Yu Tian ,&nbsp;Xiaoxia Song ,&nbsp;Xiangqin He ,&nbsp;Tao Yu ,&nbsp;Zhirong Jiang","doi":"10.1016/j.yjmcc.2025.07.010","DOIUrl":"10.1016/j.yjmcc.2025.07.010","url":null,"abstract":"<div><div>Congenital heart disease (CHD) are the predominant cause of neonatal mortality and the most prevalent congenital malformation. Additionally, CHD can impact cardiovascular health in adulthood and exacerbate cardiovascular conditions in the elderly. Emerging studies indicate that both genetic predispositions and environmental factors may contribute to the development of this condition. Notably, formaldehyde (FA), a ubiquitous environmental toxin, has been increasingly implicated in the pathophysiology of CHD through recent investigations. Earlier, we identified long noncoding RNAs (lncRNAs) that exhibited significant differential expression in rats with cardiac developmental impairments associated with FA exposure. Here our study aims to elucidate the role of lncRNA in pathological mechanisms by subjecting H9C2 cells to 24-h formaldehyde exposure or administering formaldehyde (2.0 mg/kg) to female rats and examining their offspring. We indicate that lncRNA 91,234.1 (lnc91234) plays a role in FA-induced CHD by facilitating ferroptosis via PRMT1/ASCL4/GPX4 axis, which influences the methylation of H4R3, leading to lipid peroxidation and malondialdehyde (MDA) accumulation. This research is the first to demonstrate that exposure to FA disrupts cardiac function through ferroptosis and identifies lnc91234 as a novel lncRNA that may serve as a potential therapeutic target for cardiac dysplasia and CHD by modulating myocardial function both in vivo and in vitro.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 76-90"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649630","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":"Psychosocial stress amplifies inflammation through NLRP3 Inflammasome activated by endoplasmic reticulum stress in the mouse heart","authors":"Daphne Diloretto ,&nbsp;Gaurav Sarode ,&nbsp;Phung N. Thai ,&nbsp;Jeong Han Lee ,&nbsp;Evelyn Navar ,&nbsp;Jeong eun Park ,&nbsp;Chaitali Khadilkar ,&nbsp;Ning Zong ,&nbsp;Yu Jia Dong ,&nbsp;Avni Duda ,&nbsp;Erick Romero ,&nbsp;Pablo E. Acevedo ,&nbsp;Xiao-Dong Zhang ,&nbsp;David A. Liem ,&nbsp;Imo Ebong ,&nbsp;Javier E. Lopez ,&nbsp;Heejung Bang ,&nbsp;Chao-Yin Chen ,&nbsp;Leighton Izu ,&nbsp;Martin Cadeiras ,&nbsp;Padmini Sirish","doi":"10.1016/j.yjmcc.2025.07.008","DOIUrl":"10.1016/j.yjmcc.2025.07.008","url":null,"abstract":"<div><div>Psychosocial stress (PSS) affects all humans with different intensities and is known to significantly increase inflammation and cardiovascular disease [<span><span>1</span></span>,<span><span>2</span></span>]. An amplifier of inflammation is an intracellular multiprotein complex, the inflammasome, activation of which leads to pro-inflammatory cytokines production. However, the mechanisms leading to the inflammasome activation in the heart by PSS are not well understood. Here, we identify critical upstream mechanisms leading to NLRP3 inflammasome activation via endoplasmic reticulum (ER) stress and JAK/STAT pathway. These findings reveal important mechanistic insights into possible upstream targets in controlling excessive inflammation due to PSS.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 39-43"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626573","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":"14-3-3/HIP-55 complex attenuates cardiomyocyte apoptosis","authors":"Yunqi Jiang ,&nbsp;Dannya Estau ,&nbsp;Yuhui Qiao ,&nbsp;Zijian Li","doi":"10.1016/j.yjmcc.2025.07.012","DOIUrl":"10.1016/j.yjmcc.2025.07.012","url":null,"abstract":"<div><div>Myocardial infarction (MI), a leading cause of death worldwide, results in cardiac damage mainly due to cardiomyocyte death. Early endogenous protection against cardiomyocyte death is crucial to limit infarct size and improve clinical outcomes. Previous studies have shown that 14-3-3 proteins play a vital role in cardiomyocyte survival. However, the fundamental mechanism remains unclear. Here, we revealed that 14-3-3 recruited HIP-55 forming a complex to suppress MI-induced cardiomyocyte death in response to myocardial infarction injury. The 14-3-3 partner protein-HIP-55 confers protection against MI-induced cardiomyocyte apoptosis. Mechanistically, the kinase RSK1 phosphorylates HIP-55 S269/T291 sites to promote the 14-3-3/HIP-55 complex formation which suppresses the ASK1 apoptotic pathway. Consistent with this mechanism, S269A/T291A-mutated HIP-55, which is defective in RSK1 phosphorylation and 14-3-3/HIP-55 complex formation, failed to protect against MI-induced cardiomyocyte apoptosis in vivo and in vitro. In summary, these findings demonstrate that the 14-3-3/HIP-55 complex plays a key role in cardiomyocyte survival. Targeting 14-3-3/HIP-55 may be a new therapeutic approach in the setting of acute myocardial damage.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 91-101"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659446","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":"Pyruvate kinase splice variants in fibroblasts influence cardiac remodeling after myocardial infarction in male mice","authors":"Collin K. Wells ,&nbsp;Daniel C. Nguyen ,&nbsp;Robert E. Brainard ,&nbsp;Lindsey A. McNally ,&nbsp;Maleesha De Silva ,&nbsp;Kenneth R. Brittian ,&nbsp;Lauren Garrett ,&nbsp;Madison S. Taylor ,&nbsp;Yania Martinez-Ondaro ,&nbsp;Caitlin Howard ,&nbsp;Snigdha Suluru ,&nbsp;Sujith Dassanayaka ,&nbsp;Tamer M.A. Mohamed ,&nbsp;Richa Singhal ,&nbsp;Andrew A. Gibb ,&nbsp;Pawel K. Lorkiewicz ,&nbsp;Joseph B. Moore IV ,&nbsp;Steven P. Jones ,&nbsp;Bradford G. Hill","doi":"10.1016/j.yjmcc.2025.07.005","DOIUrl":"10.1016/j.yjmcc.2025.07.005","url":null,"abstract":"<div><div>Fibroblasts are crucial for cardiac repair after myocardial infarction (MI). In response to signaling cues, they differentiate to phenotypes with robust capacities to synthesize and secrete extracellular matrix (ECM) and signaling molecules. Although activated fibroblast phenotypes are associated with pronounced changes in metabolism, it remains unclear how the metabolic network upholds the effector functions of fibroblasts in the infarcted heart. We found that two enzymes that could facilitate a phosphoenolpyruvate cycle, i.e. pyruvate kinase muscle isoform 2 (PKM2) and phosphoenolpyruvate carboxykinase 2 (PCK2), are elevated in the heart after MI. Although <em>Pck2</em> deletion had no effect on post-MI remodeling, fibroblast-specific switching of <em>Pkm2</em> to <em>Pkm1</em> (fb<em>Pkm2 → 1</em>) mitigated ventricular dilation, wall thinning, and losses in ejection fraction caused by MI. Despite these salutary effects, fb<em>Pkm2 → 1</em> switching did not alter cardiac fibrosis in vivo, nor did it affect collagen production, cytokine or chemokine secretion, myofibroblast differentiation markers, or transcriptional regulation in vitro. Nevertheless, <em>Pkm2 → 1</em> splice variant switching increased myofibroblast contractile activity as well as influenced the metabolic phenotype of fibroblasts, as shown by increased pyruvate kinase activity, higher mitochondrial respiratory capacity, and elevation in glycolytic intermediate abundance. Despite these changes, <em>Pkm2 → 1</em> switching had relatively minor effects on glucose carbon fate, as determined by stable isotope-resolved metabolomics. Nevertheless, these metabolic data demonstrate that cardiac fibroblasts exhibit minimal glucose-supported de novo glycine synthesis in vitro, yet possess high hexosamine and glucuronate biosynthetic pathway activity. Collectively, these findings reveal that fibroblast PKM isoforms influence post-MI remodeling, highlighting pyruvate kinase as a potential therapeutic target.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 11-26"},"PeriodicalIF":4.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618600","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 BAG3-HSP70-CHIP axis controls the degradation of TGFBR2 in cardiac fibroblasts","authors":"Margaretha A.J. Morsink ,&nbsp;Josephine M. Watkins ,&nbsp;Katelyn Zhu ,&nbsp;Xiaokan Zhang ,&nbsp;Lori J. Luo ,&nbsp;Barry M. Fine ,&nbsp;Bryan Z. Wang ,&nbsp;Gordana Vunjak-Novakovic","doi":"10.1016/j.yjmcc.2025.06.003","DOIUrl":"10.1016/j.yjmcc.2025.06.003","url":null,"abstract":"<div><div>Transforming Growth Factor Beta (TGF-β) is a master regulator of cardiac fibrosis, in part through the type II TGF-β receptor (TGFBR2) which initiates signaling after ligand binding. We previously identified the co-chaperone protein Bcl2-associated athanogene (BAG3) as a modulator of TGFBR2 through ubiquitination and proteasomal degradation. However, the E3 ligase of TGFBR2 was not known. Using induced pluripotent stem cell-derived cardiac fibroblasts, we identified C-terminal interacting protein of HSP70 (CHIP) as an E3 ubiquitin ligase utilized by BAG3 for TGFBR2 degradation in cardiac fibroblasts. Overexpression of CHIP significantly decreased TGFBR2 stability, while inhibition of CHIP led to increased sensitivity to TGF-β and subsequent promotion of a fibrogenic program. Further, the BAG3-HSP70 interaction was crucial to this process, as disruption of the axis increased TGFBR2 stability and sensitivity to TGF-β signaling. Together, these findings demonstrate that the BAG3-HSP70-CHIP axis controls TGF-β signaling in cardiac fibroblasts and could serve as a new therapeutic target for cardiac fibrosis.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"205 ","pages":"Pages 13-23"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248317","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":"Soluble αKlotho interacts with Hsp90aa1 to inhibit the chaperone machinery-mediated Hif1α stabilization and alleviate CKD-induced vascular calcification","authors":"Fengyang Xu ,&nbsp;Jialin Guo ,&nbsp;Yunyun Guo ,&nbsp;Jiaxin Ma ,&nbsp;Wentao Sang ,&nbsp;Xiangkai Zhao ,&nbsp;Jian Zhang ,&nbsp;Tonghui Xu ,&nbsp;Feng Xu ,&nbsp;Yuguo Chen","doi":"10.1016/j.yjmcc.2025.07.003","DOIUrl":"10.1016/j.yjmcc.2025.07.003","url":null,"abstract":"<div><div>Recent studies have highlighted the significance of soluble αKlotho in renal dysfunction-associated vascular health, however, the underlying molecular mechanisms by which soluble αKlotho maintains the vascular smooth muscle cells (VSMCs) phenotype and prevents vascular calcification remain unclear. Clinical analyses revealed an inverse correlation between circulating αKlotho levels and vascular calcification severity in early CKD patients. Recombinant protein or lentiviral vector transfection of soluble αKlotho significantly suppressed the osteogenic transdifferentiation of VSMCs in vitro. AAV-mediated overexpression of soluble αKlotho in VSMCs remarkably reduced vascular calcification without altering circulating soluble αKlotho levels or mineral metabolism in mice under a high-phosphate diet after nephrectomy. We also employed a combination of transcriptomics and proteomics approaches, as well as in vitro and in vivo vascular calcification models, and determined that soluble αKlotho specifically suppressed Hsp90aa1 activation-mediated osteogenic transdifferentiation of VSMCs and vascular calcification. The Hsp90aa1-specific inhibitor, 17-AAG, acted as an efficient therapeutic approach to attenuate vascular calcification in vivo and in vitro. Moreover, we revealed that the phosphorylation of Hsp90aa1 at Thr5/7 modulated its chaperone activity to stabilize Hif1α, thereby playing a causative role in the pathogenesis of vascular calcification. Upregulation of soluble αKlotho expression in VSMCs enhanced the interaction with Hsp90aa1 and blunted the phosphorylation of Hsp90aa1 at Thr5/7, which abolished Hsp90aa1-Hif1α axis activation in response to osteogenic induction. Our findings revealed a crucial pathway that soluble αKlotho interacts with Hsp90aa1 and suppresses the activation of the Hsp90aa1-Hif1α axis, which is involved in the osteogenic transdifferentiation of VSMCs and vascular calcification. Targeting Hsp90 may be a promising strategy for vascular calcification treatment, as various HSP90 inhibitors have been used for a range of clinical conditions.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"205 ","pages":"Pages 100-116"},"PeriodicalIF":4.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584174","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}