Circulation research最新文献

{"title":"3-Dimensional Human iPSC-Derived Cardiac Organoids for Antifibrotic Drug Screening.","authors":"Hao Zhang, Rihua Huang, Phung N Thai, Lu Ren, Rabindra V Shivnaraine, Wenjuan Zhu, Yuanyuan Dai, Wenqiang Liu, Mengjie Xie, Xiu Liu, Renke Tan, Xiaochun Yang, Xu Cao, Xuekun Wu, Matthew A Wu, Christopher Caridi, David Solow-Cordero, Joseph C Wu","doi":"10.1161/CIRCRESAHA.126.328797","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.328797","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879286","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":"RNA-Binding Protein MBNL2 Drives Cardiac Hypertrophy and Dysfunction by Facilitating TPM3 Splicing.","authors":"Yuanqi Shi, Siqi Sheng, Bin Wang, Pengcheng Lv, Jialiang Liu, Pengwei Dong, Jingyue Zhang, Jiuling Chen, Haiyu Zhang, Lin Lv, Jiale Yang, Dankun Luo, Yue Li, Zengxiang Dong","doi":"10.1161/CIRCRESAHA.125.328002","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.328002","url":null,"abstract":"<p><strong>Background: </strong>Cardiac hypertrophy is a major contributor to heart failure development, making its prevention and treatment critical for reducing heart failure-associated mortality. Although alternative splicing is recognized as a key regulatory mechanism in myocardial hypertrophy, the precise pathways involved remain incompletely defined.</p><p><strong>Methods: </strong>To investigate the role of MBNL2 (muscleblind-like protein 2) in the heart, we overexpressed MBNL2 in cardiomyocytes via adeno-associated virus serotype 9 delivery. In addition, cardiomyocyte-specific MBNL2 knockout mice were generated, and transverse aortic constriction surgery or isoproterenol injection was performed to induce cardiac hypertrophy and dysfunction in mice. The underlying mechanisms were further investigated using RNA sequencing, alternative splicing analysis, and RNA immunoprecipitation.</p><p><strong>Results: </strong>MBNL2 expression was significantly increased in the heart tissues from patients with ischemic cardiomyopathy and in mice with cardiac hypertrophy. Cardiac-specific overexpression of MBNL2 induced cardiac hypertrophy and dysfunction. Mechanistically, MBNL2 promoted exon 9 skipping of TPM3 (tropomyosin 3), generating the TPM3 isoform lacking exon 9 (TPM3-Δe9). In neonatal mouse cardiomyocytes, TPM3-Δe9 knockdown partially reduced oxidative stress and mitigated mitochondrial damage induced by MBNL2 overexpression. Adeno-associated virus serotype 9-mediated knockdown of TPM3-Δe9 partially attenuated cardiac hypertrophy in MBNL2-overexpressing mice. Notably, cardiac-specific MBNL2 knockout or TPM3-Δe9 knockdown in mice attenuated cardiac dysfunction induced by transverse aortic constriction. Further, we found that elevated TPM3-Δe9 was associated with RNF20 (ring finger protein 20) and was accompanied by reduced RNF20 interaction with NCoR1 (nuclear receptor corepressor 1), increased NCoR1 expression, and decreased PPARα (peroxisome proliferator-activated receptor alpha) signaling. The protective effects of MBNL2 or TPM3-Δe9 knockdown in hypertrophic cardiomyocytes were partially reversed by treatment with the PPARα inhibitor GW6471.</p><p><strong>Conclusions: </strong>This study uncovers a novel, critical role for MBNL2 in pathological cardiac hypertrophy through regulation of TPM3 alternative splicing and mitochondrial function, highlighting MBNL2 as a potential therapeutic target for cardiac hypertrophy and dysfunction.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873262","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":"Gut Dysbiosis Promotes Myocardial Hypertrophy via GBP2b/GBP1 in Chronic Colitis.","authors":"Yadong Wang, Jian Li, Junqing An, Vu L Ngo, Shuhan Wang, Zhenkai Hao, Chao Li, Hirohito Abo, Ye Ding, Jun Zou","doi":"10.1161/CIRCRESAHA.126.329058","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.329058","url":null,"abstract":"<p><strong>Background: </strong>Patients with inflammatory bowel disease are at increased risk of cardiovascular disease, yet the mechanisms linking chronic intestinal inflammation to cardiac dysfunction remain poorly understood. Inflammatory bowel disease is characterized by profound gut microbiota dysbiosis, which we hypothesize drives systemic immune dysregulation and contributes to cardiac dysfunction.</p><p><strong>Methods: </strong>A chronic colitis mouse model was used to assess gut microbiota dysbiosis, systemic immune cell metabolism, and cardiac remodeling. Cardiac outcomes were evaluated by echocardiography, histology, and molecular analyses. Mechanisms were examined using fecal microbiota transplantation, immune cell depletion, exosome transfer, bone marrow chimeras, RNA sequencing, coimmunoprecipitation, confocal microscopy, and siRNA-mediated gene silencing.</p><p><strong>Results: </strong>Chronic dextran sulfate sodium colitis induced cardiac dysfunction, hypertrophy, and fibrosis in mice. These changes were accompanied by sustained gut microbiota dysbiosis, metabolic reprogramming, and mitochondrial dysfunction in circulating immune cells. Fecal microbiota transfer experiments demonstrated that colitis-associated microbiota were sufficient to reprogram systemic immune cells and promote cardiac dysfunction. Immune cell depletion studies identified macrophages as key mediators of colitis-associated cardiac injury. Colitis increased systemic lipopolysaccharide translocation; bone marrow chimera experiments demonstrated that hematopoietic TLR4 (toll-like receptor 4) signaling was required for immune cell metabolic remodeling and cardiac dysfunction during chronic colitis. Transcriptomic analysis identified GBP2b (guanylate-binding protein 2b/GBP1, hereafter referred to as GBP1) as a key downstream effector of lipopolysaccharide TLR4 signaling. Upon lipopolysaccharide stimulation, GBP1 localized to mitochondria, where it interacted with DRP1 (dynamin-related protein 1) and FIS1 (fission 1 protein) to promote mitochondrial fission, oxidative stress, and enhanced immune cell migration into the heart. In addition, GBP1 was secreted via exosomes, which were taken up by cardiomyocytes and contributed to hypertrophic remodeling and cardiac dysfunction.</p><p><strong>Conclusions: </strong>These findings establish the lipopolysaccharide TLR4-GBP1 axis as a key driver of colitis-associated cardiovascular dysfunction and highlight this pathway as a promising therapeutic target for reducing cardiovascular risk in patients with inflammatory bowel disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863668","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":"Blood Metabolomic Signatures of 1-Hour Glucose Predict Cardiometabolic Risk.","authors":"Yoriko Heianza, Minghao Kou, Xuan Wang, Qi Sun, Jennifer Rood, George A Bray, Lawrence J Appel, Frank B Hu, JoAnn E Manson, Frank M Sacks, Lu Qi","doi":"10.1161/CIRCRESAHA.125.327816","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.327816","url":null,"abstract":"<p><strong>Background: </strong>Elevated 1-hour glucose levels during an oral glucose tolerance test strongly predict type 2 diabetes (T2D) and cardiovascular disease. We investigated whether the fasting blood metabolome predicting 1-hour glucose could be a target for improving β-cell function, long-term glycemic trajectories, and reducing the risks of T2D and coronary heart disease. We also investigated whether plasma microRNAs derived from key metabolic organs regulate changes in a metabolomic risk score (MRS) for predicting 1-hour glucose.</p><p><strong>Methods: </strong>Untargeted blood metabolomics and a frequently sampled 75-g oral glucose tolerance test were performed in participants from the OmniCarb trial (n=162). In an independent weight-loss dietary intervention trial (POUNDS Lost [Preventing Overweight Using Novel Dietary Strategies]), temporal changes in MRS and plasma microRNAs measured by genome-wide sequencing were analyzed. In addition, associations of MRS at baseline and its 10-year changes with long-term risk of incident T2D and coronary heart disease were prospectively investigated in the NHS (Nurses' Health Study).</p><p><strong>Results: </strong>We created a fasting blood MRS for predicting 1-hour glucose (Pearson <i>r</i>=0.8) and found significant associations with half-day (diurnal) postprandial glucose excursions and insulin secretion after 5-week controlled feeding interventions varying in carbohydrate amount and glycemic index. In the POUNDS Lost trial, diet-induced changes in MRSs were related to 2-year trajectories of glucose metabolism; circulating microRNAs regulating cardiometabolic abnormalities were pivotal factors influencing these changes. In the NHS, women in the top 20% of MRS had a multivariate-adjusted relative risk of 3.80 (95% CI, 2.22-6.51) for T2D and 1.48 (95% CI, 1.04-2.12) for coronary heart disease compared with those in the lowest 20%. In addition, 10-year increases in plasma metabolites related to 1-hour glucose were linearly associated with a higher risk of T2D.</p><p><strong>Conclusions: </strong>Our findings indicate that fasting blood metabolomic signatures predicting elevated 1-hour glucose reflect disease pathophysiology and could be targets for preventing T2D and coronary heart disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":18.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863689","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":"Soluble TREM2: Biomarker, Bystander, or Causal Mediator in Atherosclerosis?","authors":"Jingjing Tang, Karin E Bornfeldt","doi":"10.1161/CIRCRESAHA.126.329360","DOIUrl":"10.1161/CIRCRESAHA.126.329360","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 6","pages":"e329360"},"PeriodicalIF":18.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839399","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":"Soluble TREM2 Drives Atherosclerosis via HSP90β-Dependent Myeloid Inflammation.","authors":"Xiaoqing Guo, Xiaoming Liu, Jie Yu, Mengting Qin, Shengnan Wang, Jiaojiao Chen, Dailiang Jiang, Yuhang Feng, Jiangnan Yu, Xiaojun Xu, Ling Mao","doi":"10.1161/CIRCRESAHA.125.327491","DOIUrl":"10.1161/CIRCRESAHA.125.327491","url":null,"abstract":"<p><strong>Background: </strong>Chronic inflammation is a key driver of atherosclerotic cardiovascular disease. Notably, anti-inflammatory therapies have demonstrated efficacy in reducing cardiac events. We previously reported that TREM2 (triggering receptor expressed on myeloid cells 2) promotes foam cell formation in atherosclerosis. Elevated levels of sTREM2 (soluble TREM2) have been observed in the plasma of patients with atherosclerosis. This study sought to investigate the pathological role of sTREM2 in the progression of atherosclerosis, elucidate its underlying mechanistic pathways, and propose potential targeted therapeutic interventions.</p><p><strong>Methods: </strong>Plasma sTREM2 levels were measured in patients with carotid atherosclerosis and in apolipoprotein E-deficient (<i>Apoe</i>^-/-) mice. To study the functional role of sTREM2, we administered recombinant sTREM2 to <i>Apoe</i>^-/- mice and used macrophage-specific <i>Hsp90ab1</i> knockout mice (<i>Hsp90ab1</i>^Mac-KO). Mechanistic pathways were investigated using immunoprecipitation-mass spectrometry, and surface plasmon resonance imaging was used to identify sTREM2 antagonists.</p><p><strong>Results: </strong>Plasma sTREM2 levels correlated with atherosclerotic burden in both humans and mice. Exogenous sTREM2 administration exacerbated plaque progression in <i>Apoe</i>^-/- mice, an effect abolished in <i>Hsp90ab1</i>^Mac-KO mice. Mechanistically, sTREM2 binds to HSP90β (heat shock protein 90 beta), enhancing its interaction with the IKKs (IκB kinase complex), thereby activating the IκBα (inhibitor of nuclear factor-κB)/NF-κB (nuclear factor-κB) P65 pathway. This activation potentiates monocyte adhesion and chemotaxis and enhances macrophage inflammatory activation signatures in atherosclerotic lesions-effects that were reversed on myeloid-specific <i>Hsp90ab1</i> deletion. Additionally, we identified 3-bromopyruvate as a small-molecule antagonist that selectively disrupts the sTREM2/HSP90β interaction and attenuates atherosclerosis.</p><p><strong>Conclusions: </strong>sTREM2 promotes proatherogenic myeloid recruitment and macrophage inflammatory activation via HSP90β-dependent NF-κB activation. Genetic and pharmacological approaches establish the sTREM2/HSP90β axis as a druggable target, with 3-bromopyruvate demonstrating translational potential for atherosclerosis therapy.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327491"},"PeriodicalIF":18.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599712","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":"Methylmalonate, a Metabolic Scar in the Diabetic Heart.","authors":"Ettore Vanni, Sandrine Horman, Luc Bertrand","doi":"10.1161/CIRCRESAHA.126.329228","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.126.329228","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 6","pages":"e329228"},"PeriodicalIF":18.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839369","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":"Microglia Drive Hypothalamic Inflammation in HFpEF Through Extracellular Vesicles Released From the Heart.","authors":"Hossein Ardehali","doi":"10.1161/CIRCRESAHA.126.329362","DOIUrl":"10.1161/CIRCRESAHA.126.329362","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 6","pages":"e329362"},"PeriodicalIF":18.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839401","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000767","DOIUrl":"https://doi.org/10.1161/RES.0000000000000767","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 6","pages":"e000767"},"PeriodicalIF":18.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839439","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":"Distinct Urinary Protein Signatures in Adolescent Blood Pressure Phenotypes.","authors":"Loreen Thürmann, Anke Seegebarth, Andrea von Berg, Dietrich Berdel, Sibylle Koletzko, Joachim Heinrich, Tamara Schikowski, Irina Lehmann, Marie Standl, Saskia Trump","doi":"10.1161/CIRCRESAHA.126.328246","DOIUrl":"10.1161/CIRCRESAHA.126.328246","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328246"},"PeriodicalIF":18.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548065","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}