Circulation research最新文献

{"title":"Obesity Increases Atherosclerosis Susceptibility via an Intertissue miR-30e-SLC7A11 Axis","authors":"Chen Wang,Jianqing She,Xiaoli Qian,Haoyu Wu,Wenyang Hao,Xiao Liang,Ning Guo,Xulei Dai,Fangzhou He,Songyang He,Jin Zhang,Yuyang Lei,Xiaozhen Zhuo,Hongbing Li,Yongbai Luo,Kai Deng,Yi Liu,Shanshan Gao,Xiao Yuan,Hui Liu,Ting Bai,Ying Xiong,John Y-J. Shyy,Zu-Yi Yuan","doi":"10.1161/circresaha.126.328493","DOIUrl":"https://doi.org/10.1161/circresaha.126.328493","url":null,"abstract":"BACKGROUND: With obesity as a risk factor for atherosclerotic disease, recent research suggests that adipose tissue in obese animal models and humans can generate endocrine-like molecules that affect arterial health. Previous studies showed that microRNA-30e (miR-30e) levels are elevated in atherosclerosis and solute carrier family 7 member 11 (SLC7A11), a cystine/glutamate transporter, is involved in atherogenesis. However, whether an endocrine-like link between the adipose-derived miR-30e-5p and SLC7A11 in the vascular endothelium can lead to obesity-caused atherosclerosis is unknown. METHODS: miRNA data mining and reverse transcription-polymerase chain reaction validations were used to demonstrate the positive association among serum levels of miR-30e-5p, obesity, and coronary arterial disease in human patients. Transcriptomics (bulk RNA sequencing and single-nucleus RNA sequencing), metabolomics, and in silico analysis were used to establish a miR-30e-5p–SLC7A11 regulation of central carbon metabolism, mitochondrial and endothelial cell (EC) function. Mouse models with EC-specific Slc7a11 knockout (EC- Slc7a11 −/− ) and gain- or loss-of- function of miR-30e-5p were used to elucidate the detrimental role of this endocrine-like axis in obesity-related atherosclerosis. RESULTS: The level of adipocyte-derived miR-30e-5p was significantly upregulated in obese human patients with coronary artery disease and in obese and atherosclerotic mice. Mediated through serum exosomes, the adipocyte-generated miR-30e-5p targeted SLC7A11 mRNA in vascular ECs. SLC7A11 deficiency due to miR-30e-5p targeting dysregulated glutamate/cystine metabolism, increased glycolysis, reduced oxidative phosphorylation, and impaired mitochondrial function. The EC dysfunction could be rectified by SLC7A11 overexpression or miR-30e-5p antagonism. Administration of exogenous miR-30e-5p or white adipose tissue-derived exosomes phenocopied the increased atherosclerosis in EC- Slc7a11 −/− mice. In contrast, miR-30e-5p antagomir or GW4869 treatment reduced atherosclerosis in Apoe −/− and ob/ob mice. CONCLUSIONS: Our multiomics approaches demonstrate that the adipose-derived miR-30e-5p downregulated SLC7A11 mRNA in ECs via tissue crosstalk. The resulting EC dysfunction led to obesity-related atherosclerosis in mice. These findings underscore a causality between obesity and atherosclerosis in the context of cardiovascular-kidney-metabolic syndrome.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"7 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923196","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000769","DOIUrl":"https://doi.org/10.1161/RES.0000000000000769","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 7","pages":"e000769"},"PeriodicalIF":18.0,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929187","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":"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":"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":"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}

{"title":"Metabolomic Profiles and Changes During the 20 Years Preceding Heart Failure.","authors":"Jiangtao Li, Shusi Ding, Zhao Yang, Mingdan Wang, Xuan Deng, Xueting Sun, Wenting Lu, Pingping Jia, Yan Liu, Yuhan Zhang, Jun Cai, Lemin Zheng, Yue Qi, Jing Liu","doi":"10.1161/CIRCRESAHA.126.328542","DOIUrl":"10.1161/CIRCRESAHA.126.328542","url":null,"abstract":"<p><strong>Background: </strong>Longitudinal metabolomic studies can refine understanding of heart failure (HF) progression and enable precision prevention. This study aims to identify serum metabolites associated with HF risk via longitudinal metabolomic analysis, delineate their dynamic trajectories, and explore metabolite profiles in populations with different metabolic disorders.</p><p><strong>Methods: </strong>This study analyzed longitudinal serum metabolomic data from 4774 serum samples from 1728 HF-free participants in the Chinese Multi-Provincial Cohort Study Metabolomics Project at 4 time points over a 20-year follow-up. Intensity models and Cox proportional-hazards models identified metabolites associated with HF risk. Latent variable mixed-effects models evaluated metabolite trajectories.</p><p><strong>Results: </strong>Of the 784 detected metabolites, 23 were associated with HF risk at a false discovery rate-adjusted <i>P</i><0.05, including 9 not previously reported in relation to HF. The HF risk-associated metabolites exhibited 4 distinct trajectory clusters and corresponding biological trends. Most metabolites that showed positive associations with HF risk remained relatively stable throughout the 20-year follow-up period, whereas metabolites that were negatively associated with HF risk generally exhibited a declining trend. The levels of these 23 metabolites in the group who developed HF began to diverge from the levels in the non-HF group >5 years before clinical HF diagnosis, with most changes initiating 15 to 20 years before clinical manifestation. Populations with different metabolic disorders exhibited distinct metabolite profiles related to HF. The HF-associated metabolites were primarily involved in energy metabolism and the vasodilatory response among individuals with hypertension, lipotoxic effects and oxidative stress among those with obesity, and inflammatory processes and glucotoxic mechanisms among individuals with dysglycemia.</p><p><strong>Conclusions: </strong>This longitudinal metabolomic study identifies HF-associated metabolite profiles, characterizes their changes during the 20 years preceding clinical diagnosis, and reveals heterogeneity across individuals with different metabolic disorders, thereby informing future biomarker and intervention research.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328542"},"PeriodicalIF":18.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148577377","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":"Methylmalonate Overload Despite Glycemic Control Drives Diabetic Heart Damage.","authors":"Shanjie Wang, Miao Yan, Yiying Zhang, Fan Tang, Ye Wang, Junchen Guo, Zhanchao Chen, Xiaoxuan Liu, Zhaoying Li, Rongze Lu, Yan Cui, Guanpeng Ma, Pengyan Wu, Yuanyuan Huang, Yige Liu, Zeng Wang, Xing Luo, Hengxuan Cai, Yanjiao Shen, Wen Ge, Zhuozhong Wang, Shuang Yang, Dongdong Sun, Shaohong Fang, Bo Yu","doi":"10.1161/CIRCRESAHA.125.327192","DOIUrl":"10.1161/CIRCRESAHA.125.327192","url":null,"abstract":"<p><strong>Background: </strong>Despite optimal glycemic control, the heart failure burden remains substantial in diabetic patients. Metabolic remodeling is involved in this process, yet our current understanding is still in its infancy. Methylmalonic acid (MMA) is conventionally viewed as a marker of cobalamin (Cbl) deficiency. Paradoxically, MMA elevation-related cardiovascular mortality is more pronounced in diabetic patients with normal or high Cbl levels. This study investigated the mechanisms and translational significance of this contradictory MMA accumulation in the diabetic heart.</p><p><strong>Methods: </strong>We analyzed serum Cbl, MMA, and cardiac biomarkers in 12 751 participants and characterized Mmut (methylmalonyl-CoA mutase; a key enzyme in MMA catabolism) expression in failing human hearts with diabetes. Cardiomyocyte-specific Mmut knockout and Mmut-overexpressing mice were subjected to high-fat diet/streptozotocin-induced diabetes. Molecular mechanisms were elucidated using ¹³C-isotope tracing, RNA sequencing, immunoprecipitation, and biolayer interferometry.</p><p><strong>Results: </strong>Elevated serum MMA was significantly associated with subclinical heart damage and adverse outcomes in diabetic adults, even in the absence of Cbl deficiency. Cardiac MMA overload and decreased protein expression of Mmut were observed in humans and mice with diabetes. Notably, MMA dysmetabolism preceded detectable cardiac dysfunction in diabetic mice and persisted even after glycemic normalization. Mechanistically, the hyperglycemic memory-associated molecule miR-499 binds to Mmut mRNA, suppressing its expression and driving MMA accumulation. Mmut deficiency amplified cardiac MMA overload and exacerbated disturbances in glycolipid metabolism and mitochondrial quality control, whereas adeno-associated virus-mediated Mmut overexpression attenuated cardiac MMA load and adverse remodeling in diabetic mice. Isotope tracing identified isoleucine and valine as the primary sources of cardiac MMA under diabetic conditions. Branched-chain amino acid-restricted diets alleviated diabetes-induced MMA accumulation and heart damage. Crucially, Cbl supplementation failed to alleviate MMA overload in diabetic mice, even at high doses or with activated forms. Strikingly, metformin, an established risk factor for Cbl deficiency, mitigated MMA-induced heart damage through dual mechanisms: activating AMPK (AMP-activated protein kinase)-dependent mitochondrial quality control to enhance tolerance to MMA, and directly promoting Mmut-Cbl cooperation to enhance MMA clearance.</p><p><strong>Conclusions: </strong>This study provides a foundation for understanding diabetes-related MMA dysmetabolism as a trigger for subclinical heart damage resistant to glycemic control and Cbl supplementation. Our findings challenge the prevailing clinical consensus regarding the impacts of Cbl and metformin use on MMA elevation in diabetic management.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327192"},"PeriodicalIF":18.0,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599771","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}