Circulation research最新文献

{"title":"Lipoprotein(a) Drives Platelet Hyperactivity Through Oxidized Phospholipids-CD36.","authors":"Emily Horner, Lih T Cheah, Thomas Palmer-Dench, Jawad S Khalil, Mary McKay, Fraser L Macrae, Mark T Kearney, Amanda J Unsworth, Khalid M Naseem","doi":"10.1161/CIRCRESAHA.126.329174","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.329174","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time to Look Closer: Mast Cell Glycobiology at the Cardio-Immune Interface","authors":"Lukas J. Weiss,Ulrich Hofmann","doi":"10.1161/circresaha.126.329306","DOIUrl":"https://doi.org/10.1161/circresaha.126.329306","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"3 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloid Activator Protein-1 Complex Contributes to Salt-Sensitive Hypertension.","authors":"Taseer Ahmad, Mohammad Saleem, Ashley Pitzer Mutchler, Lale A Ertuglu, Quanhu Sheng, Claude F Albritton, Alexandria Porcia Haynes, Mert Demirci, Selam Desta, Mohd Mabood Khan, Ronald McMillan, Jeremiah Afolabi, Annet Kirabo","doi":"10.1161/CIRCRESAHA.125.327976","DOIUrl":"10.1161/CIRCRESAHA.125.327976","url":null,"abstract":"<p><strong>Background: </strong>Salt-sensitivity of blood pressure is an independent risk factor for cardiovascular diseases, yet the molecular pathways linking dietary sodium to immune activation and hypertension remain poorly defined. We previously demonstrated that sodium entry into antigen-presenting cells via the ENaC (epithelial sodium channel) promotes inflammation and salt-sensitivity of blood pressure. AP-1 (activator protein-1; c-FOS, FOSB, c-JUN, JUNB, JUND) regulates inflammatory signaling, but its role in salt-sensitivity of blood pressure has not been elucidated. We hypothesized that high salt drives AP-1-mediated inflammatory activation in antigen-presenting cells, contributing to immune dysfunction and hypertension.</p><p><strong>Methods: </strong>Using SV129 salt-sensitive mice, we assessed blood pressure responses and profiled immune cell phenotypes under normal- and high-salt conditions by flow cytometry. RNA-seq was performed on human monocytes exposed to high salt in vitro. In a clinical study, we enrolled prehypertensive subjects and performed an inpatient salt-loading/depletion protocol to characterize AP-1 gene expression signatures in salt-sensitive versus salt-resistant individuals. To test causality, we adoptively transferred PBMCs from salt-sensitive, salt-resistant, and salt-sensitive individuals pretreated with T5224 (a selective AP-1 inhibitor) into immunodeficient NSG-(<i>K</i>^<i>b</i><i>D</i>^<i>b</i>)^null (<i>IA</i>)^null humanized mice, followed by assessment of blood pressure, vascular reactivity, kidney function, and immune infiltration.</p><p><strong>Results: </strong>High salt robustly induced AP-1 gene expression in murine monocytes. In humans, salt-sensitive but not salt-resistant subjects exhibited concordant increases in AP-1 gene expression and blood pressure during salt loading. PBMCs from salt-sensitive individuals promoted greater tissue infiltration, AP-1 activation, and immune-mediated renal and vascular dysfunction in humanized mice compared with PBMCs from salt-resistant individuals. Strikingly, pretreatment of salt-sensitive PBMCs with T5224 abrogated these effects, preserving normal renal and vascular function despite high-salt exposure.</p><p><strong>Conclusions: </strong>These findings identify AP-1 as a key transcriptional driver linking dietary sodium, immune activation, and salt-sensitivity of blood pressure. Targeting AP-1 signaling mitigates immune-mediated renal and vascular injury, highlighting a novel mechanistic pathway and a therapeutic target for salt-sensitive hypertension.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327976"},"PeriodicalIF":18.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mast Cell St8sia1 Is a Glyco-Epigenetic Checkpoint Driving Cardiac Remodeling.","authors":"Changzuan Zhou, Lisheng Fu, Tianyou Yuan, Fangfang Li, Fanhuan Tang, Xiaoyu Wu, Yutong Ye, Longzhe Gao, Chenyang Jin, Qitong Zhang, Liang Xu, Shaowen Liu, Songwen Chen, Jun Li","doi":"10.1161/CIRCRESAHA.125.328171","DOIUrl":"10.1161/CIRCRESAHA.125.328171","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic immune-cardiac crosstalk underlies maladaptive remodeling in chronic heart failure, yet therapies directly targeting this axis are lacking. Glycoconjugates, which are crucial for signal transduction and extracellular matrix integrity, represent an underexploited therapeutic avenue. This study sought to define the role of glycoconjugate-metabolizing enzymes at the immune-cardiac interface and evaluate their translational potential.</p><p><strong>Methods: </strong>We performed integrative analyses of bulk and single-cell RNA sequencing data from failing human and mouse hearts. Employing mouse models of pressure overload (transverse aortic constriction) and ischemia-reperfusion, we used global and mast cell (MC)-specific gene deletion, bone-marrow chimeras, and pharmacological neutralization. Mechanistic insights were gained through multiomics profiling, including RNA-seq, ATAC-seq, CUT&Tag, and proteomics.</p><p><strong>Results: </strong>The ganglioside GD3 synthase, St8sia1, was selectively induced in cardiac MCs during pathological remodeling in both mice and humans. MC-specific or hematopoietic deletion of <i>St8sia1</i> preserved ventricular function, attenuated fibrosis, and markedly reduced neutrophil and Ly6C⁺ monocyte recruitment after transverse aortic constriction and ischemia-reperfusion. Therapeutic neutralization of GD3 with the clinical-grade monoclonal antibody R24 improved cardiac function and diminished scar formation after ischemia-reperfusion. Mechanistically, GD3 bound specific histone variants, such as H2A.Z and H3.3C, thereby reprogramming chromatin accessibility to activate proinflammatory and profibrotic transcriptional programs in MCs. Consequently, GD3 inhibition suppressed MC degranulation, disrupted pathogenic MC-cardiomyocyte/fibroblast crosstalk, and preserved reparative macrophage populations.</p><p><strong>Conclusions: </strong>The MC-restricted St8sia1-GD3 axis functions as a glyco-epigenetic checkpoint driving maladaptive cardiac remodeling. Targeting this axis represents a translatable immunomodulatory strategy to prevent the progression to chronic heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328171"},"PeriodicalIF":18.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148673264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural ERRα Activator Formononetin Ameliorates Anthracycline Cardiotoxicity via Metabolic Improvement.","authors":"Xiaoping Wang, Guanjing Ling, Yan Wei, Weili Li, Yi Zhang, Ziyi Yin, Kai Wei, Qian Chen, Lei Dong, Yun Chen, Wei Wang, Qi Qiu, Yong Wang","doi":"10.1161/CIRCRESAHA.126.329042","DOIUrl":"10.1161/CIRCRESAHA.126.329042","url":null,"abstract":"<p><strong>Background: </strong>Anthracycline-induced cardiotoxicity (AIC) limits life-saving chemotherapy and is driven by early metabolic remodeling. The nuclear receptor ERRα (estrogen-related receptor α) is a master regulator of cardiac energy metabolism, but the temporal dynamics of its downregulation, its causal role in AIC pathogenesis, and whether it can be pharmacologically activated to confer protection remain undefined.</p><p><strong>Methods: </strong>We performed temporal protein analysis in a porcine AIC model. Using cardiomyocyte-specificgain- and loss-of-function mouse models, we assessed the causal role of ERRα. Mechanistic studies included ChIP-qPCR, reporter assays, and microscale thermophoresis to investigate the natural compound formononetin. Human breast cancer patient-derived organoids were used to evaluate anticancer activity.</p><p><strong>Results: </strong>ERRα expression was selectively downregulated in AIC pig hearts and cardiac tissue from chemotherapy-treated patients. Temporal analysis in pigs revealed that ERRα reduction occurred at the subclinical (6-week) stage, preceding overt cardiac dysfunction. Cardiomyocyte-specific ERRα overexpression activated mitochondrial gene programs, enhanced fatty acid oxidation, and preserved systolic function after doxorubicin challenge, whereas ERRα knockdown exacerbated bioenergetic failure and cardiac dysfunction. Through drug screening, we identified formononetin as a potent and selective ERRα agonist. Formononetin enhanced ERRα transcriptional activity, improved mitochondrial metabolism, and protected against AIC in both murine and porcine models. Mechanistically, ChIP-qPCR demonstrated increased ERRα occupancy at target gene promoters, and microscale thermophoresis confirmed direct binding of formononetin to the ERRα/PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) complex, indicating allosteric stabilization. Finally, in human breast cancer patient-derived organoids, formononetin alone reduced viability and proliferation, and combined with doxorubicin further enhanced antitumor efficacy.</p><p><strong>Conclusions: </strong>ERRα downregulation is a causal early event in the pathogenesis of AIC. Formononetin acts as a first-in-class selective ERRα activator that improves cardiac metabolism and function while retaining anticancer activity, supporting its potential as a dual-action cardioprotective agent during anthracycline therapy.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e329042"},"PeriodicalIF":18.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK5RAP3-Mediated Mitochondrial RQC Alleviates Pathological Cardiac Hypertrophy.","authors":"Yazhi Peng, Wenwen Cai, Tailai Du, Yi Zheng, Yiling Yao, Gang Dai, Jialing Wu, Yan Li, Jiangui He, Yugang Dong, Jing-Song Ou, Chen Liu, Xin He, Zhan-Peng Huang","doi":"10.1161/CIRCRESAHA.125.328184","DOIUrl":"10.1161/CIRCRESAHA.125.328184","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have revealed heterogeneity among ribosomes. Pathological cardiac hypertrophy is characterized by profound alterations in translation. However, how ribosome heterogeneity contributes to this process remains largely unclear.</p><p><strong>Methods: </strong>We used translating ribosome affinity purification coupled with mass spectrometry to profile ribosome-interacting proteins. Cardiomyocyte-specific gene manipulation was achieved through either genetic knockout or adeno-associated virus-mediated overexpression. Pathological cardiac hypertrophy was induced by transverse aortic constriction surgery in vivo and by phenylephrine stimulation in vitro.</p><p><strong>Results: </strong>The cardiomyocyte-specific ribosome proteomics indicated dynamic alterations in ribosome-interacting proteins during pathological hypertrophy. Notably, multiple proteins associated with ribosome stalling were detected in the ribosome-interactome of hypertrophic hearts. Among these, we verified that CDK5RAP3 (CDK5 regulatory subunit-associated protein 3) exhibited the most specific ribosome binding in hypertrophic hearts. CDK5RAP3 was upregulated and recruited to ribosomes during pathological hypertrophy. It promoted RPL26 (ribosomal protein L26) UFMylation and ribosome-associated quality control on the mitochondrial surface. In vitro, CDK5RAP3 knockdown exacerbated cardiomyocyte hypertrophy induced by phenylephrine, whereas its overexpression attenuated it. In vivo, cardiomyocyte-specific CDK5RAP3 knockout promoted, while adeno-associated virus-mediated overexpression suppressed pathological cardiac hypertrophy induced by transverse aortic constriction. Mechanistically, ribosome stalling on the mitochondrial surface was exacerbated in hypertrophic hearts of both humans and mice, which was associated with impaired mitochondrial protein import. CDK5RAP3 enhanced ribosome-associated quality control, alleviated ribosome stalling, and restored mitochondrial protein import, thereby improving mitochondrial function. Notably, mitochondrial import of PDP1 (pyruvate dehydrogenase phosphatase catalytic subunit 1) was maintained by CDK5RAP3-mediated ribosome-associated quality control. Knockdown of PDK (pyruvate dehydrogenase kinase) 1/2, functional antagonists of PDP1, reversed cardiomyocyte hypertrophy caused by CDK5RAP3 deficiency.</p><p><strong>Conclusions: </strong>This study identifies CDK5RAP3-mediated ribosome-associated quality control on the mitochondrial surface as a critical protective mechanism that preserves protein import and mitochondrial function during pathological cardiac hypertrophy.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328184"},"PeriodicalIF":18.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the ER: UFMylation and Mitochondrial Ribosome Quality Control","authors":"Shelly Marinberg,Izhak Kehat","doi":"10.1161/circresaha.126.329481","DOIUrl":"https://doi.org/10.1161/circresaha.126.329481","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"11 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Desmoplakin Mutations in Cardiac Fibroblasts Cause TGFβ1-Mediated Pathological Fibrogenesis in Desmoplakin Cardiomyopathy Via Beclin-1 Regulation.","authors":"Chuanyu Wei, Weinian Shou, Shing-Fai Chan, Ardan M Saguner, Corinna Brunckhorst, Firat Duru, Joseph E Marine, Cynthia A James, Hugh Calkins, Daniel P Judge, Huei-Sheng Vincent Chen","doi":"10.1161/CIRCRESAHA.124.325512","DOIUrl":"10.1161/CIRCRESAHA.124.325512","url":null,"abstract":"<p><strong>Background: </strong>Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy. Among arrhythmogenic cardiomyopathies, pathogenic <i>DSP</i> (desmoplakin) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. <i>DSP</i> variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remains unknown.</p><p><strong>Methods: </strong>Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including the heart. We first used RNA-seq genome-wide analyses to generate cardiac fibroblast-like, induced pluripotent stem cell-derived MSCs from normal donors and patients with arrhythmogenic cardiomyopathy and <i>DSP</i> mutations. We then studied the fibrogenic responses of cardiac MSCs to TGFβ1 (transforming growth factor β1) using Western/Co-IP, autophagy assays, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR.</p><p><strong>Results: </strong>TGFβ1 induced excessive accumulation of VIM (vimentin)/fibrillar collagens and over-activated fibrotic genes in <i>DSP</i>-mutant MSCs when compared with normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFβ1. <i>DSP</i>-mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered BECN1 (beclin-1) from activating autophagy and CAV1 (caveolin-1)-mediated endocytosis. Decreased autophagy caused collagen accumulation, and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes (<i>COL1A1</i>, <i>COL3A1</i>, and fibronectin [<i>FN</i>]) via heightened p38 activity after TGFβ1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of <i>DSP</i> mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expression.</p><p><strong>Conclusions: </strong>Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e325512"},"PeriodicalIF":18.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13574352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiomyocyte-Specific Inhibition of p53 Signaling as a Therapeutic Strategy for Arrhythmogenic Right Ventricular Cardiomyopathy Type 5.","authors":"Laura Lalaguna, Marina López-Olañeta, Carlos Torroja, Carlos Relaño-Rupérez, Carlos Fernández-Sellers, Fátima Sánchez-Cabo, Juan Pablo Ochoa, Esther Zorio, Pablo García-Pavía, Enrique Lara-Pezzi","doi":"10.1161/CIRCRESAHA.126.328827","DOIUrl":"10.1161/CIRCRESAHA.126.328827","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328827"},"PeriodicalIF":18.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13574339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: uPAR/suPAR Signaling and Organ Crosstalk in Cardiovascular-Kidney-Metabolic Syndrome","authors":"Salim S. Hayek,Stuart E. Dryer","doi":"10.1161/res.0000000000000768","DOIUrl":"https://doi.org/10.1161/res.0000000000000768","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"39 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}