Circulation research最新文献

{"title":"GPR146 Facilitates Blood Pressure Elevation and Vascular Remodeling via PIEZO1.","authors":"Zhenzhen Chen,Haizeng Zhang,Wendong Li,Qianhui Ling,Wenwen Cong,Yue Deng,Ke Chen,Shuangyue Li,Changting Cui,Wenjie Wang,Bin Geng,Jun Cai","doi":"10.1161/circresaha.125.326288","DOIUrl":"https://doi.org/10.1161/circresaha.125.326288","url":null,"abstract":"BACKGROUNDHypertension is a prevalent chronic disease worldwide. Elevated hydrostatic pressure (HP) is the main feature of hypertension. GPCRs (G-protein-coupled receptors) are crucial for vascular tone and a significant pharmacological target for drug development. Here, we aimed to identify the key GPCR under high HP, and explore its role and mechanism in hypertension and vascular remodeling.METHODSFirst, RNA-seq was performed under high HP and identified the highly expressed GPCR-GPR146. Furthermore, global knockout GPR146 mice, vascular smooth muscle cell (SMC)-specific knockin and knockout GPR146 mice were used to explore its function in hypertension. Next, an HP loading system ex vivo was established to evaluate the role of GPR146 in response to HP. Vascular SMC-specific Piezo1 mice were constructed to investigate the relationship between GPR146 and PIEZO1. In vitro, GPR146-mediated downstream signaling transduction was detected by proximity ligation assay and bioluminescence resonance energy transfer. Finally, the therapeutic effect of hypertension was detected by GPR146 neutralization antibody injection.RESULTSUnder high HP, we identified a highly expressed GPCR-GPR146 in vascular SMCs by RNA-seq and confirmed it in the arterial media of patients with hypertension and animal models. Functionally, overexpression or deletion of Gpr146 in SMCs demonstrated that GPR146 facilitated vascular contraction, promoted vascular SMCs phenotype switching from a contractile phenotype to synthetic phenotype and proinflammation phenotype, and led to blood pressure elevation, vascular remodeling, and cardiac hypertrophy aggravation. In vitro, GPR146 was upregulated in an HP-dependent manner. Mechanistically, GPR146 is a Gαs-coupled GPCR activating the cAMP-CREB1 (cAMP response element-binding protein 1) signaling cascade. Notably, GPR146 upregulated PIEZO1 expression by enhancing CREB1 binding to the PIEZO1 promoter region. Piezo1 deletion in SMCs blocked Gpr146-induced blood pressure elevation and vascular dysfunction. GPR146 neutralization antibody injection markedly alleviates angiotensin II-induced hypertension and vascular remodeling.CONCLUSIONSCollectively, GPR146 coupled with Gαs and activating the cAMP-CREB1-PIEZO1 signaling pathway contributes to hypertension and vascular remodeling. Blocking GPR146 is an effective therapeutic strategy for hypertension.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"1 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594032","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":"GPLD1 Attenuates Heart Failure via Dual Membrane Localization to Inhibit uPAR.","authors":"Wenjing Yu,Zhen Guo,Huimin Liang,Dinghu Ma,Chenjia Lin,Zeyu Li,Jiaying Yu,Anahita Ataran,Ali Javaheri,Zhiping Liu,Duanping Sun,Peiqing Liu,Jing Lu","doi":"10.1161/circresaha.124.325623","DOIUrl":"https://doi.org/10.1161/circresaha.124.325623","url":null,"abstract":"BACKGROUNDDespite the established role of GPLD1 (glycosylphosphatidylinositol-specific phospholipase D1) in age-related impairments, its involvement in cardiovascular diseases remains unclear.METHODSWe analyzed GPLD1 transcript and protein levels in heart tissues from patients with heart failure (HF) and murine HF models. Genetic approaches, including cardiac-specific depletion, overexpression, or mutation of GPLD1, alongside intramyocardial injection of adeno-associated virus 9-mediated GPLD1 overexpression or its shRNA transduction, were used to assess the functional role of GPLD1 in transverse aortic constriction-induced HF mouse models. Proteomic profiling identified candidate binding targets, which were validated using methods including proximity ligation assay and coimmunoprecipitation. uPAR (urokinase-type plasminogen activator receptor) overexpression or shRNA targeting uPAR was performed to interrogate mechanistic pathways. Subcellular localization of GPLD1 was investigated through membrane lipid analysis and subcellular fractionation of plasma membrane and mitochondrial compartments. Cardiomyocytes were transfected with pRS426GFP-2×PH (PLC [phospholipase C] δ) to monitor phosphatidylinositol 4,5-bisphosphate levels. Cytosolic and mitochondrial calcium levels, mitochondrial permeability transition pore opening, and oxygen consumption rate were measured to evaluate cellular homeostasis and bioenergetics.RESULTSGPLD1 levels were elevated in patients with HF and murine models. Cardiac-specific GPLD1 depletion exacerbated cardiac dysfunction and hypertrophy, while its overexpression ameliorated these effects, depending on enzymatic activity. uPAR was identified as a potential binding target for GPLD1, and viral-mediated uPAR transduction completely abolished the protective effects of GPLD1 following transverse aortic constriction surgery. Mechanistically, GPLD1 was anchored to the plasma membrane and outer mitochondrial membrane via phosphatidylinositol 4,5-bisphosphate to cleave the glycosylphosphatidylinositol anchor of uPAR, thereby maintaining calcium homeostasis and mitochondrial function, and ultimately ameliorating cardiac dysfunction. Conversely, excess uPAR led to a decrease in phosphatidylinositol 4,5-bisphosphate levels, preventing GPLD1 from localizing to these membranes and causing it to disperse in the cytoplasm.CONCLUSIONSOur studies identify GPLD1 as an endogenous protective factor against HF and suggest that it may be a promising therapeutic target for cardiac dysfunction and HF.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"702 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586561","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":"Unraveling Skeletal Muscle Insulin Resistance: Molecular Mechanisms and the Restorative Role of Exercise.","authors":"Katie L Whytock, Bret H Goodpaster","doi":"10.1161/CIRCRESAHA.125.325532","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.325532","url":null,"abstract":"<p><p>Skeletal muscle is essential for movement and maintaining energy homeostasis and is the primary tissue for insulin-stimulated glucose uptake. Skeletal muscle is composed of various cell types that help to govern the delivery, transport, and metabolism of nutrients to and within the tissue. Dysregulation of these processes can result in impaired insulin-stimulated glucose uptake and dysglycemia-insulin resistance and type 2 diabetes. Acute exercise and chronic exercise training provide a robust stimulus to improve nutrient delivery, nutrient transport into a cell, and subsequent storage and oxidation to help improve insulin sensitivity. This review details the molecular mechanisms of skeletal muscle insulin resistance and how exercise counteracts these defects, highlighting the key role of exercise in muscle health and disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 2","pages":"184-204"},"PeriodicalIF":16.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559383","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":"Exercise in Inherited Cardiomyopathies: Optimizing the Dose-Response Curve.","authors":"Eleanor E Rye, Amy M Mitchell, Celine F Santiago, Andre La Gerche, Diane Fatkin","doi":"10.1161/CIRCRESAHA.125.326396","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.326396","url":null,"abstract":"<p><p>Exercise is generally considered beneficial for cardiovascular health, but for patients with inherited cardiomyopathies, exercise can be a source of anxiety due to concerns about arrhythmia risk and disease progression. In the general population, exercise avoidance can impact cardiometabolic health and diminished fitness is a risk factor for heart failure. At the other extreme, sustained high levels of exercise in competitive endurance athletes have been associated with an increased risk of some arrhythmias. Defining optimal threshold levels for exercise participation is not straightforward and one-size-fits-all recommendations are unlikely to be successful. In the context of inherited cardiomyopathies, the impact of exercise on myocardial function and arrhythmias depends on factors such as exercise frequency, intensity, and duration, as well as the type of cardiomyopathy, underlying genotype, and other unique intrinsic traits in each individual. This review outlines current knowledge with respect to the impact of exercise in hypertrophic, arrhythmogenic, and dilated cardiomyopathies based on studies in human cohorts and animal models. Several disease-specific and genotype-specific risk factors are highlighted, although our understanding of these factors remains incomplete. Importantly, although exercise activities remain restricted for those with high-risk features, emerging evidence suggests that moderate-to-high levels of exercise may be safe and beneficial for many patients. Harnessing the cardioprotective power of exercise holds enormous promise for expanding personalized strategies for cardiomyopathy treatment and prevention.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 2","pages":"316-334"},"PeriodicalIF":16.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559377","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":"Animal Models of Exercise and Cardiometabolic Disease.","authors":"Gengfu Dong, Terence E Ryan, Karyn A Esser","doi":"10.1161/CIRCRESAHA.124.325704","DOIUrl":"10.1161/CIRCRESAHA.124.325704","url":null,"abstract":"<p><p>Cardiometabolic diseases, encompassing cardiovascular and metabolic disorders, represent a significant global health challenge, driven in part by the rising prevalence of obesity and type 2 diabetes. Exercise offers profound benefits in mitigating the progression and impact of cardiometabolic diseases by improving glucose homeostasis, body composition, and cardiovascular function. However, gaps remain in our understanding of the molecular mechanisms underlying these benefits and how to optimize exercise prescriptions for cardiometabolic disease. Animal models are indispensable tools for unraveling these mechanisms and translating findings to human health for improved management of these conditions. Rodent exercise models (eg, treadmill running and wheel running) dominate preclinical research, while resistance training models and high-intensity interval training models have gained in popularity in recent years. This review provides a comprehensive evaluation of existing animal models for cardiometabolic disease and exercise, highlighting their strengths, limitations, and translational relevance. We emphasize the critical need for research to support our mechanistic understanding of the multiorgan health benefits for the prevention of cardiometabolic diseases. In addition, we also highlight the need for research applying well-defined exercise interventions with preclinical disease models to provide translational data to guide future clinical applications for patients with cardiometabolic diseases.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 2","pages":"139-162"},"PeriodicalIF":16.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559356","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":"Paradox of Exercise and Coronary Artery Calcification: Potential Underlying Mechanisms.","authors":"Jeffrey J Hsu, Yin Tintut, Linda L Demer","doi":"10.1161/CIRCRESAHA.125.326011","DOIUrl":"10.1161/CIRCRESAHA.125.326011","url":null,"abstract":"<p><p>Regular exercise is widely known to exert beneficial effects on the cardiovascular system. Despite the widely accepted and numerous benefits of exercise, whether there is an upper limit to these benefits is unclear, particularly with regard to atherosclerotic disease. Observational cohort studies over the past 2 decades have identified a consistent signal of increased coronary artery calcification in older men, who have been exposed to high volumes of endurance exercise over their lifetime. The clinical ramifications of these findings are not fully known, as outcomes studies in these athletic populations are needed, but given the strong associations of coronary artery calcification with adverse cardiovascular events, a deeper mechanistic understanding of the link between endurance exercise and coronary artery calcification is needed. In this review, we describe the possible underlying mechanisms that may explain this conundrum of the athlete calcification paradox at the molecular and cellular levels.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 2","pages":"335-349"},"PeriodicalIF":16.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559381","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":"Cardiovascular Aging and Exercise: Implications for Heart Failure Prevention and Management.","authors":"Vinayak Subramanian, Wesley J Tucker, Anthony E Peters, Bharathi Upadhya, Dalane W Kitzman, Ambarish Pandey","doi":"10.1161/CIRCRESAHA.125.325531","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.325531","url":null,"abstract":"<p><p>A demographic shift toward an aging population is occurring worldwide. Commensurate with this trend, age-related diseases are also rising. Although aging is an immutable part of life, biological aging is a highly heterogeneous process influenced by health-related behaviors, genetics, and the environment. The biological effects of aging are evident across all organ systems. Some individuals demonstrate an accelerated aging phenotype, which is associated with substantial morbidity and mortality. Moreover, common cardiovascular conditions, such as heart failure with preserved ejection fraction, can be conceptualized as a consequence of accelerated aging. Physical activity and exercise training modify the biological effects of accelerated aging considerably. They are associated with various salutary benefits and have emerged as potent therapeutics in disease states characterized by the accelerated aging phenotype. In this state-of-the-art review, we discuss the age-related changes observed in cardiovascular and peripheral tissues, the implications of age acceleration, and the effectiveness and mechanisms of physical activity and exercise training to curb the deleterious effects of aging and improve outcomes.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 2","pages":"205-230"},"PeriodicalIF":16.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559375","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":"Benefits of Cardiac Rehabilitation: Mechanisms to Restore Function and Clinical Impact.","authors":"Abdulla A Damluji, Corey R Tomczak, Stephanie Hiser, Deirdre E O'Neill, Parag Goyal, Quinn R Pack, Stephen J Foulkes, Todd M Brown, Mark J Haykowsky, Dale M Needham, Daniel E Forman","doi":"10.1161/CIRCRESAHA.125.325705","DOIUrl":"10.1161/CIRCRESAHA.125.325705","url":null,"abstract":"<p><p>Cardiac rehabilitation (CR) has evolved from foundations as a postmyocardial infarction mobilization strategy for patients who were typically unstable, into a comprehensive, multidisciplinary program for most patients with cardiovascular disease aimed at optimizing cardiovascular health, reducing morbidity, and enhancing functional recovery. Although contemporary CR patients are now usually more stable from a cardiovascular perspective, needs have expanded for comprehensive approaches to exercise, lifestyle, care coordination, risk factor modification, and stress management. Furthermore, contemporary CR patients now typically include older adults who are contending with cardiovascular disease in the context of multimorbidity, frailty, sarcopenia, sensory limits, and cognitive impairment. The physiological mechanisms underlying exercise intolerance in cardiovascular disease include impairments in cardiac output, vascular function, and skeletal muscle metabolism and relate to elemental biological mechanisms that are common to all 3 as well as to noncardiovascular disease and aging. CR provides an important opportunity to address such aggregate risk. Nonetheless, CR remains underutilized, particularly by older adults, women, and those struggling with cognitive impairments, frailty, logistics, and social barriers to care. Emerging strategies, such as home-based and hybrid CR models, resistance training, and digital health technologies, are expanding the potential for access and effectiveness. Future research brings important opportunities to hone personalized CR strategies tailored to contemporary patient populations, including optimized exercise prescriptions as well as pharmacological, nutritional, and technological adjuncts. Related prospects to distinguish the biological mechanisms underlying patient-preferred clinical end points (eg, independence, quality of life) remain critical to augmenting CR's value in the contemporary therapeutic landscape.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 2","pages":"255-272"},"PeriodicalIF":16.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559374","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":"Implications of HFpEF Definitions Unveiled by Rest and Exercise Hemodynamics.","authors":"Isabela Landsteiner, Takenori Ikoma, Ashvita Ramesh, Joseph Campain, Laura P Cohen, Charles C Hardin, Rajeev Malhotra, Gregory D Lewis","doi":"10.1161/CIRCRESAHA.125.326504","DOIUrl":"10.1161/CIRCRESAHA.125.326504","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"357-359"},"PeriodicalIF":16.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12227208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265394","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":"Introduction to the Compendium on Cardiopulmonary Disease and Exercise: Molecular to Clinical Mechanisms.","authors":"Robert E Gerszten, Ravi V Shah","doi":"10.1161/CIRCRESAHA.125.326910","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.326910","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 2","pages":"119"},"PeriodicalIF":16.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559379","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}