Circulation research最新文献

{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000754","DOIUrl":"https://doi.org/10.1161/RES.0000000000000754","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 10","pages":"e000754"},"PeriodicalIF":16.2,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834351","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":"Correction to: Novel Mechanisms of Exosome-Mediated Phagocytosis of Dead Cells in Injured Heart.","authors":"Mallikarjun Patil, Sherin Saheera, Praveen K Dubey, Asher Kahn-Krell, Prem Kumar Govindappa, Sarojini Singh, Sultan Tousif, Qinkun Zhang, Hind Lal, Jianyi Zhang, Gangjian Qin, Prasanna Krishnamurthy","doi":"10.1161/RES.0000000000000753","DOIUrl":"https://doi.org/10.1161/RES.0000000000000753","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 10","pages":"e000753"},"PeriodicalIF":16.2,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834429","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":"Inhibiting RhoA Activation Via GDP-State Stabilization to Relieve Heart Failure.","authors":"Mengzhu Xue, Yingquan Liang, Zhen Yuan, Xiangning Liu, Longfeng Chang, Yongzhi Wang, Peijia Xu, Tingting Zhang, Hewei Jiang, Zijie Zhao, Jingqiu Liu, Shanshan Ruan, Tianyu Ye, Xuelian Pang, Wenyi Mei, Jiawen Wang, Xiaoqian Sun, Huijuan Wang, Jian Cui, Yao Zu, Xudong Lin, Zhenjiang Zhao, Rui Wang, Hong Huang, Cheng Luo, Shengce Tao, Jing Wang, Yajun Duan, Lili Zhu, Huifang Tang, Jian Zhang, Yong Wang, Chun Li, Honglin Li","doi":"10.1161/CIRCRESAHA.125.327107","DOIUrl":"10.1161/CIRCRESAHA.125.327107","url":null,"abstract":"<p><strong>Background: </strong>Given the persistently high morbidity and mortality of heart failure (HF), targeting myocardial remodeling, particularly pathological hypertrophy and fibrosis, has become a major therapeutic priority. RhoA (Ras homolog gene family member A), a small GTPase governing cytoskeletal reorganization and cell migration, plays a pivotal role in this process. However, RhoA has long been considered undruggable because of its high-affinity binding to GDP/GTP and the absence of well-defined druggable pockets.</p><p><strong>Methods: </strong>Structural analyses comparing RhoA-GTP and RhoA-GDP conformations, combined with surface plasmon resonance-based screening, were used to identify a RhoA inhibitor. The underlying mechanism was validated in cultured cells and 3-dimensional myocardial tissue models. Therapeutic efficacy was assessed across multiple species of HF models and supported by multiomics analyses linking RhoA activation to human HF. Key findings were further confirmed by multiplex immunohistochemistry and pulldown assays in human heart specimens.</p><p><strong>Results: </strong>We identified an unrecognized cryptic pocket adjacent to GDP in RhoA. A natural product, AH001, selectively occupied this pocket and interacted with GDP, thereby stabilizing the interaction between RhoA and its endogenous inhibitor, RhoGDIα (Rho GDP-dissociation inhibitor 1). AH001 suppressed downstream signaling by reducing MRTFA (myocardin-related transcription factor A) nuclear translocation and downregulating fibrosis- and hypertrophy-related proteins. Moreover, AH001 disrupted pathological crosstalk between <i>Mrtfa</i>+ cardiomyocytes and fibroblasts. Consequently, AH001 markedly attenuated myocardial remodeling in multiple HF animal models, as well as in 3-dimensional myocardial tissue models.</p><p><strong>Conclusions: </strong>These findings establish pharmacological inhibition of RhoA activation as a viable strategy to mitigate myocardial remodeling in HF and provide a conceptual framework for developing reversible inhibitors against previously undruggable small GTPases.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327107"},"PeriodicalIF":16.2,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484872","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":"T-World: A New Majesty Arises in the Realm of Cardiac Models.","authors":"Jan P Kucera","doi":"10.1161/CIRCRESAHA.126.328634","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.328634","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 10","pages":"e328634"},"PeriodicalIF":16.2,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834373","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":"Harnessing Immune Pathways for Stroke Recovery: Overcoming Challenges to Clinical Translation.","authors":"Alex Peh, Ali Ahmadi, Ahmed Refaat, Marcel Michla, Jonathan Noonan, Guido Stoll, Karlheinz Peter","doi":"10.1161/CIRCRESAHA.125.326981","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.326981","url":null,"abstract":"<p><p>Despite advances in acute care, stroke remains a leading cause of death and long-term disability worldwide, with limited treatment options to improve recovery after stroke. Traditionally, the management of ischemic stroke has mostly focused on early reperfusion, yet growing evidence highlights a central role for inflammation in both acute and long-term pathophysiology of stroke. The inflammatory response post-stroke is complex and dynamic, beginning with early intravascular activation of platelets and neutrophils (thrombo-inflammation), followed by microglial activation and the subsequent infiltration of peripheral immune cells, which together paradoxically contribute to tissue repair but can also worsen tissue injury. Importantly, this evolving understanding opens new therapeutic opportunities. However, efforts to target inflammation in stroke have yielded limited clinical success, as many strategies that showed promise in preclinical studies have failed to translate into beneficial outcomes. Here, we systematically review the role of inflammatory responses in stroke, integrating insights from both experimental and clinical studies. We highlight the roles of key immune cell populations and signaling pathways in mediating tissue injury and repair, also discussing the progress and limitations of inflammation-targeting clinical trials. We further address translational challenges, including optimal timing of intervention, mechanistic target validity, and the relevance of preclinical models. Finally, we explore emerging approaches, including targeting thrombo-inflammation, modulation of the gut-brain axis, reverse translation, and adaptive data-driven trial designs as potential strategies to refine therapy development to improve stroke outcomes. These insights provide a foundation for advancing the long-elusive goal of clinically translating immune therapy into effective stroke recovery treatments.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 10","pages":"e326981"},"PeriodicalIF":16.2,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834392","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":"AH001: A New Drug Targeting RhoA in Heart Failure.","authors":"Vi B Nguyen, Michael S Kapiloff","doi":"10.1161/CIRCRESAHA.126.328631","DOIUrl":"10.1161/CIRCRESAHA.126.328631","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"138 10","pages":"e328631"},"PeriodicalIF":16.2,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13155368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834433","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":"Adipose-Derived FAM19A5 Inhibits Both Vascular Calcification and Osteoporosis in Mice.","authors":"Zhao Dong, Yang Shiyu, Huan Wang, Jiazi Zhang, Nan Xie, Rongbo Dai, Siting Zhang, Zeyu Cai, Zhiqing Li, Shirong Zhu, Jinwei Wang, Biao Zhou, Jihong Kang, Fang Yu, Hua Meng, Yi Fu, Luxia Zhang, Lu Zhang, Song Chunli, Wei Kong","doi":"10.1161/CIRCRESAHA.125.327708","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.327708","url":null,"abstract":"<p><strong>Background: </strong>Vascular calcification and osteoporosis often co-occur during postmenopause, end-stage renal disease, advancing age, and diabetes, leading to increased mortality and significant challenges in therapy. FAM19A5 (family with sequence similarity 19 [chemokine (C-C motif)-like], member A5), as a novel protective adipokine, has been identified to suppress postinjury neointima formation. However, the involvement of adipose-derived FAM19A5 in vascular calcification and osteoporosis remains unclear.</p><p><strong>Methods: </strong>A cross-sectional study was conducted to assess the relationship among circulating FAM19A5, coronary artery calcification, and osteoporosis. Adipose-specific FAM19A5 transgenic mice and AAV8 (adeno-associated virus serum type 8)-adipo-shFAM19A5 were employed to study gain or loss of function of FAM19A5 in 2 distinct mouse models: ovariectomy followed by Vitamin D3 overload (OVX-VitD3) and adenine diet. Calcium assays, micro-CT, Western blot, RT-qPCR, luciferase reporter assays, and ChIP-qPCR were performed to clarify the phenotype and elucidate the molecular mechanisms. Finally, administration of AAV8-adipoq-FAM19A5 and S1PR2 (sphingosine 1-phosphate receptor 2) global knockout mice was used to investigate their therapeutic effects.</p><p><strong>Results: </strong>Circulating FAM19A5 was negatively correlated with coronary artery calcification and osteoporosis in patients and mouse models. Adipose-specific FAM19A5 transgenic mice exhibited milder aortic calcification and preserved bone mass via S1PR2 in both OVX-VitD3 and adenine diet models. Although adipose-specific knockdown of FAM19A5 aggravates aortic calcification and bone mass loss. Interestingly, FAM19A5 mitigated vascular smooth muscle cells' calcification by activating S1PR2-Gi-PKA signaling and promoted mice osteoblasts differentiation by triggering S1PR2-Gq-PKCδ (protein kinase C delta isoform) signaling. Finally, administration of AAV8-adipoq-FAM19A5 effectively rescued vascular calcification and osteoporosis, but exerted no beneficial effects in S1PR2 knockout mice.</p><p><strong>Conclusions: </strong>Adipose-derived FAM19A5 plays an essential role in orchestrating vascular calcification and osteoporosis through the selective activation of S1PR2. Our findings provide novel insight into the previously unexplored role of adipose tissue in maintaining vascular-bone homeostasis. FAM19A5-S1PR2 may be considered as a potential therapeutic strategy for vascular calcification and osteoporosis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834411","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":"Chronic Erythrocyte NO Production Accelerates Atherosclerosis by Increasing SMC De Novo Lipogenesis.","authors":"Beichen Sun, Rajinikanth Gogiraju, Franziska Greulich, Frank Kumi, Iman Ghasemi, Magdalena L Bochenek, Sven Pagel, Emiel P C van der Vorst, My Phung Khuu, Kateryna Moiko, Luisa Renner, Payal Guliani, Wolfram Ruf, Stefan Porubsky, Christoph Reinhardt, Ingrid Fleming, Laura Bindila, Philipp Lurz, Katrin Schäfer","doi":"10.1161/CIRCRESAHA.125.327866","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.327866","url":null,"abstract":"<p><strong>Background: </strong>Endothelial dysfunction is an early event in atherosclerosis development and is centrally linked with insufficient endothelial NO production. However, chronically increased NO levels, including NO from other cellular sources, may induce endothelial dysfunction. Here, we studied how chronically elevated NO production from erythrocytes, achieved by genetic deletion of ARG1 (arginase-1), impacts smooth muscle cell (SMC) lipid accumulation and atherosclerosis progression.</p><p><strong>Methods: </strong>Primary aortic SMCs from mice lacking ARG1 in red blood cell (RBC.ARG1-knockout [KO]) were subjected to RNA-sequencing, lipidomic, metabolic, and molecular analyses; atherosclerosis burden was quantified en face and at the aortic root.</p><p><strong>Results: </strong>Increased lipid droplet formation in SMCs from RBC.ARG1-KO mice was observed using brightfield and electron microscopy and confirmed by Oil Red O and BODIPY lipid dye staining. RNA sequencing revealed the simultaneous overexpression of genes regulating lipid uptake (<i>Cd36</i>), catabolism (<i>Cpt1a</i>), and de novo lipogenesis (<i>Acaca</i>, <i>Fasn</i>) in RBC.ARG1-KO SMCs, and inhibiting fatty acid translocase (CD36), ACC (acetyl-CoA [coenzyme A] carboxylase), or fatty acid synthase prevented the lipid accumulation in RBC.ARG1-KO SMCs. Increased expression of CD36 downstream of NO and overactivated sGC (soluble guanylyl cyclase)-cyclic guanosine monophosphate signaling was identified as a mediator of increased lipid uptake in RBC.ARG1-KO SMCs. Loss of PDE (phosphodiesterase) 2A, coupling cyclic guanosine monophosphate with cyclic adenosine monophosphate and PKA (protein kinase A) activation, was also observed, resulting in AMPK (5' AMP-activated protein kinase) inhibition, thus unlocking acetyl-CoA carboxylase, catalyzing the rate-limiting step in fatty acid synthesis. Inhibiting PDE2A recapitulated the RBC.ARG1-KO SMC phenotype, while inhibiting PKA or ATP generation from cyclic adenosine monophosphate abrogated the lipid droplet accumulation in RBC.ARG1-KO SMCs. Increased Oil Red O-positive aortic atherosclerosis burden in hypercholesterolemic apolipoprotein E-deficient RBC.ARG1-KO mice was confirmed by histology and elevated levels of polyunsaturated long-chain cholesterol esters in aortic atheroma by mass spectrometry lipidomics.</p><p><strong>Conclusions: </strong>Our findings show the importance of erythrocyte-derived NO for metabolically reprogramming SMCs toward increased fatty acid uptake and lipogenesis, and identify PDE2A as a molecular switch linking chronically activated NO signaling with lipid accumulation and atheroma progression.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811417","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":"Early ApoA-I Treatment Prevents Post-Surgical Atherosclerotic Plaque Destabilization.","authors":"Dominique M Boucher, Victoria Lorant, Ryan P Barney, Benjamin Bhunu, Scott M Gordon, Mireille Ouimet","doi":"10.1161/CIRCRESAHA.125.328179","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.328179","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811504","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":"Dynamin 2 Regulates Mitochondrial Mitotic Fission in Pulmonary Hypertension.","authors":"Asish Dasgupta,Kuang-Hueih Chen,Danchen Wu,V Siddartha Yerramilli,Patricia D A Lima,Ashley Y Martin,Rachel E T Bentley,Benjamin P Ott,Tanvi Nandani,Jeffrey D Mewburn,Lian Tian,Ruaa Al-Qazazi,Isaac M Emon,Pierce Colpman,Lindsay Jefferson,Curtis Noordhof,Oliver Jones,Charles C T Hindmarch,Stephen L Archer","doi":"10.1161/circresaha.125.327028","DOIUrl":"https://doi.org/10.1161/circresaha.125.327028","url":null,"abstract":"BACKGROUNDDRP1 (dynamin-related protein 1) mediates mitochondrial fission and permits rapid cell cycle progression in hyperproliferative cells by coordinating nuclear and mitochondrial division, a process called mitotic fission. However, DRP1 alone appears insufficient to complete fission, and the link between fission and cell cycle progression is unknown. We hypothesize that DNM2 (dynamin 2) interacts with DRP1 to complete mitochondrial fission and regulate cell cycle progression. We show that DNM2 is upregulated in pulmonary artery smooth muscle cells (PASMCs) in human and rodent pulmonary arterial hypertension (PAH) PASMCs, contributing to disease pathophysiology.METHODSMitochondrial morphology, protein colocalization, and fission were assessed using stimulated emission depletion microscopy, protein interactions by immunoprecipitation, and transcriptomics by RNA sequencing. DNM2 was quantified in PASMC and lungs from patients with PAH and rats with PH, induced by monocrotaline or sugen5416/hypoxia. siDNM2's effects on cell proliferation, cell cycle progression, and apoptosis were assessed by flow cytometry. Single-cell RNA sequencing was performed on publicly available data sets. siDNM2 was nebulized to monocrotaline- and sugen5416/hypoxia-PH rats, and disease regression was quantified by cardiac catheterization and histology.RESULTSDNM2 is increased in PAH PASMC. DNM2 interacts with DRP1 via its GTPase domain, permitting mitochondrial translocation and promoting fission. siDNM2 inhibits fission and cell proliferation and increases apoptosis. siDNM2 causes G1/G0 blockade by downregulating the RGCC (regulator of cell cycle) with downstream effects on CDK (cyclin-dependent kinase) 4, cyclin D1, and p27kip1. Conversely, augmenting DNM2 in normal PASMC induces fission and accelerates proliferation. Upregulation of DNM2 in PAH is due to decreased miR-124-3p and activation of STAT3 (signal transducer and activator of transcription 3). An miR-124-3p-STAT3-DNM2-DRP1-RGCC pathway accelerates mitotic fission and is upregulated in PASMC, airway epithelium, endothelial cells, fibroblasts, and macrophages in PAH. Nebulized siDNM2 regresses established PAH in vivo in rats of both sexes.CONCLUSIONSDNM2 is a mediator in the terminal steps of DRP1-dependent fission and constitutes a novel therapeutic target in PAH.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"59 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147753153","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}