Circulation research最新文献

{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000734","DOIUrl":"https://doi.org/10.1161/RES.0000000000000734","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 9","pages":"1137-1139"},"PeriodicalIF":16.2,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257554","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":"CCL21 Enhances Platelet Activation and Atherothrombosis via CCR7 Activation.","authors":"Xin Liu,Peng Zhang,Zhexun Lia,Haichu Yu,Yonghong Li,Junjie Guo,Ning Zhang,Shimo Dai,Zhiyong Qi,Junbo Ge","doi":"10.1161/circresaha.125.326784","DOIUrl":"https://doi.org/10.1161/circresaha.125.326784","url":null,"abstract":"BACKGROUNDThe homeostatic chemokine CCL21 (C-C motif chemokine ligand 21) is abnormally elevated in coronary artery disease. Plasma CCL21 levels have been found to be independently associated with adverse outcomes after acute coronary syndrome. However, the specific effects of CCL21 on coronary artery disease-associated platelet activation and thrombosis remain poorly understood.METHODSWe examined the effects of CCL21 on platelet activation, spreading, clot retraction, in vitro shear stress-induced thrombus formation, in vivo arterial thrombus formation, middle cerebral artery occlusion-induced brain injury, and myocardial ischemia-reperfusion injury. We also investigated the underlying mechanisms and the therapeutic impacts of a CCL21 antibody on platelet activation and in vivo thrombosis in atherosclerosis.RESULTSCCL21 potentiated agonist-induced platelet activation, including aggregation, dense granule release, P-selectin exposure, integrin αIIbβ3 activation, spreading, and clot retraction. Furthermore, CCL21 enhanced in vivo thrombosis, whole blood thrombus formation, and middle cerebral artery occlusion-induced brain injury. Mechanistically, CCL21 binds to platelet CCR7 (C-C motif chemokine receptor 7), a G-protein-coupled receptor previously unreported in platelets, activating Gi and G13 signaling pathways to enhance platelet activation. A CCL21 antibody attenuated platelet activation and inhibited in vivo thrombosis in patients with coronary artery disease and atherosclerotic ApoE-/- mice. In addition, this antibody mitigated microvascular thrombosis, safeguarding the hearts of atherosclerotic ApoE-/- mice from severe ischemia-reperfusion injury.CONCLUSIONSCCL21 enhances platelet activation and atherothrombosis by binding to platelet CCR7 and thus activating downstream Gi and G13 signaling pathways. A CCL21 antibody can counteract these effects in the context of coronary artery disease, supporting its potential as a preventive therapy for thrombotic complications.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"126 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254487","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 the Link Between Cardiomyocyte Endoreplication and Hypertrophy.","authors":"Zhe Yu,Thomas Moore-Morris,Sylvia M Evans","doi":"10.1161/circresaha.125.327130","DOIUrl":"https://doi.org/10.1161/circresaha.125.327130","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"26 1","pages":"1182-1184"},"PeriodicalIF":20.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254490","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":"Cardiomyocyte-Restricted Expression of Progerin Confers Cardiac Hypertrophy.","authors":"Tuerdi Subati,Dennis P Buehler,Lin Zhong,Francis J Miller,Vineet Agrawal,Jonathan D Brown","doi":"10.1161/circresaha.125.326423","DOIUrl":"https://doi.org/10.1161/circresaha.125.326423","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"24 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246903","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":"When Resident Macrophages Call, Fibroblasts Answer: CCL24-CCR3 in Fibrosis.","authors":"Abraham L Bayer,Pilar Alcaide","doi":"10.1161/circresaha.125.327362","DOIUrl":"https://doi.org/10.1161/circresaha.125.327362","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"45 1","pages":"1157-1159"},"PeriodicalIF":20.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254489","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":"Adaptation to Elevated Mitochondrial Calcium Is Distinct in the Left and Right Ventricles.","authors":"Shanmugasundaram Pakkiriswami,Jae Hwi Sung,Kshama R Shah,Ulas Ozkurede,Megan K Sumera,Feng Feng,Hector Chapoy Villanueva,Eun Suh Cho,Andrea Torniainen,Jop van Berlo,Gyorgy Hajnoczky,Kurt W Prins,Julia C Liu","doi":"10.1161/circresaha.125.326221","DOIUrl":"https://doi.org/10.1161/circresaha.125.326221","url":null,"abstract":"BACKGROUNDMitochondrial ATP production, essential for cardiomyocyte function, is regulated by mitochondrial Ca2+ (mtCa2+). The primary route for mtCa2+ influx is the mitochondrial calcium uniporter complex. The mitochondrial calcium uniporter complex subunit MICU (mitochondrial calcium uptake) 1 limits mtCa2+ uptake, preventing mtCa2+ overload. Although elevated mtCa2+ has been observed in multiple diseases including heart failure, its effects on heart function remain elusive.METHODSTo investigate the impact of elevated mtCa2+ in adult hearts, we generated a mouse model with cardiomyocyte-specific tamoxifen-inducible Micu1 deletion (Micu1cKO). Cardiac function was assessed through echocardiography. Mitochondria, adult cardiomyocytes, and tissue extracts were isolated from the left ventricle (LV) and right ventricle (RV) for comprehensive analysis at multiple time points ranging from 1 to 9 weeks post-tamoxifen injection.RESULTSAcute MICU1 deficiency resulted in increased mtCa2+ accompanied by reduced mitochondrial respiration in both the RV and LV. Contractile function, which was diminished in both ventricles initially, remained reduced in the RV upon prolonged MICU1 deficiency. In contrast, the LV exhibited signs of recovery over time, including restored ejection fraction concurrent with normalization of mtCa2+ levels. This pattern was mirrored in cardiomyocyte contractility. In Micu1cKO RV, mtCa2+ remained elevated, likely contributing to oxidative stress. As a potential mechanism underlying LV-specific recovery, EMRE (essential MCU regulator), an mitochondrial calcium uniporter complex subunit that promotes mtCa2+ uptake, was found to be downregulated only in the LV. This suggested that the LV initiated a compensatory response to elevated mtCa2+, while the RV remained impacted. Supporting this, proteomics analysis indicated a divergent proteomic signature in Micu1cKO RV. Follow-up experiments suggested enhanced EMRE degradation in Micu1cKO LV mediated by m-AAA proteases through a PKA (protein kinase A)-regulated mechanism. In MICU1-deficient neonatal cardiomyocytes, pharmacological PKA inhibition was sufficient to decrease EMRE levels. Analysis of LV tissues from patients with dilated cardiomyopathy suggested that this pathway may be relevant in human DCM.CONCLUSIONSWhile elevated mtCa2+ disrupted cardiac function in both ventricles, it induced an LV-specific adaptive response that suppressed mtCa2+ intake, contributing to the recovery of mitochondrial and cardiac function. The absence of this pathway in the RV has implications for therapeutics targeting RV dysfunction, a key determinant of mortality in heart failure.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"30 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145235755","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":"S1P-Loading of CAD-HDL Restored Impaired HDL-Mediated Cardioprotection.","authors":"Marcel Benkhoff,Jens Vogt,Nathalie H Schröder,Hao Hu,Lisa Dannenberg,Petra Keul,Philipp Mourikis,Tobias Zeus,Philipp Wollnitzke,Malte Kelm,Bodo Levkau,Amin Polzin","doi":"10.1161/circresaha.125.327041","DOIUrl":"https://doi.org/10.1161/circresaha.125.327041","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"99 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209078","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":"IGFBP2 Mediates Human iPSC-Cardiomyocyte Proliferation in a Cellular Contact-Dependent Manner.","authors":"Soah Lee,Paul Heinrich,Daniel Lee,Yongwon Kang,Harley Robinson,Sean J Humphrey,Jihye Yun,William R Goodyer,Jan W Buikema,David T Paik,Francisco X Galdos,Boyoung Kim,Nadjet Belbachir,Sungjin Min,Seung-Woo Cho,Jaecheol Lee,Alessandra Moretti,Joseph C Wu,James Hudson,Sean M Wu","doi":"10.1161/circresaha.125.326522","DOIUrl":"https://doi.org/10.1161/circresaha.125.326522","url":null,"abstract":"BACKGROUNDInduction of cardiomyocyte proliferation in situ represents a promising strategy for myocardial regeneration following injury. However, cardiomyocytes possess intrinsic inhibitory mechanisms that attenuate pro-proliferative signaling and constrain their expansion. We hypothesized that cell-cell contact is a key suppressor of cardiomyocyte proliferation. We aimed to delineate the underlying molecular pathways to enable sustained proliferation in 3-dimensional contexts.METHODSHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured at varying plating densities to examine the impact of cell-cell contact on cell cycle activity. Phosphoproteomic profiling was performed in sparse versus dense cultures to identify signaling alterations. Conditioned media from sparse cultures were interrogated using a human growth factor array to identify secreted pro-proliferative factors.RESULTShiPSC-CM proliferation increased proportionally with plating density until intercellular contacts were established, at which point proliferation was suppressed. Dense cultures exhibited enhanced adherens junction assembly, sarcomeric organization, and contractile function. Increased cell-cell contact in dense conditions attenuated nuclear translocation of β-catenin and reduced TCF/LEF transcriptional activity, providing a mechanistic basis for the reduced hiPSC-CM proliferation. Disruption of adherens junctions or sarcomere assembly via siRNA-mediated knockdown of N-cadherin or α-actinin, respectively, resulted in increased cell cycle activation of hiPSC-CMs, but this was not sufficient to drive division of hiPSC-CMs. Additional screening for putative secreted growth factors in the conditioned media from sparsely plated hiPSC-CMs revealed the enrichment of IGFBP2, which was sufficient to drive hiPSC-CM division in the presence of cell-cell contact in 3-dimensional constructs.CONCLUSIONSOur findings demonstrate that cell-cell contact inhibits hiPSC-CM proliferation through adherens junction formation, sarcomeric assembly, and reduced IGFBP2 secretion. Importantly, exogenous supplementation of IGFBP2 can overcome cell contact-mediated inhibition of hiPSC-CM proliferation and facilitate the growth of 3-dimensional cardiac tissue. These insights provide valuable implications for advancing cardiac tissue engineering and regenerative therapies.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"93 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194828","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":"Macrophage DNases Limit Neutrophil Extracellular Trap-Mediated Defective Efferocytosis in Atherosclerosis.","authors":"Umesh Kumar Dhawan,Tanwi Vartak,Hanna Englert,Stefan Russo,Luiz Ricardo C Vasconcellos,Aarushi Singhal,Rahul Chakraborty,Karran Kiran Bhagat,Ciaran McDonnell,Mary Connolly,Edward Mulkern,Martin O'Donohoe,Mathias Gelderblom,Thomas Renne,Catherine Godson,Eoin Brennan,Manikandan Subramanian","doi":"10.1161/circresaha.125.326353","DOIUrl":"https://doi.org/10.1161/circresaha.125.326353","url":null,"abstract":"BACKGROUNDNeutrophil extracellular traps (NETs) contribute to atherosclerosis progression and are linked to adverse clinical outcomes such as myocardial infarction and stroke. Although the triggers of NET formation in plaques are known, the mechanisms governing DNase-mediated NET clearance and how these are disrupted during atherosclerosis remain unclear. Moreover, the consequences of impaired NET clearance on disease progression are not known.METHODSLow-density lipoprotein receptor knockout (Ldlr-/-) mice with hematopoietic cell-specific deletion of DNase1 and DNase1L3 were fed a Western-type diet for 16 weeks to examine the impact of loss of DNase activity and the subsequent NET accumulation on advanced atherosclerosis. The effect of NETs on macrophage efferocytosis was examined in vitro and in the mouse peritoneal cavity and atherosclerotic plaque in vivo. To identify the signaling pathway impairing the NET-induced DNase response, in vitro assays were performed using selective endoplasmic reticulum stress pathway inhibitors, and the findings were validated in murine and human atherosclerotic tissues.RESULTSLack of DNase secretion by macrophages led to accumulation of NETs in local tissues, including atherosclerotic plaques. Persisting NETs in turn promoted cleavage of the efferocytosis receptor MerTK, resulting in defective macrophage efferocytosis and increased atherosclerotic plaque necrosis. In vitro screening identified endoplasmic reticulum stress-induced activation of the PERK (protein kinase R-like endoplasmic reticulum kinase)-ATF (activating transcription factor) 4 signaling axis in atherogenic macrophages as a key driver of impaired DNase secretion, leading to delayed NET clearance and their pathological persistence. Treatment of human atherosclerotic plaques and Ldlr-/- mice with integrated stress response inhibitor, a selective PERK inhibitor, restored vascular DNase secretion and facilitated NET clearance.CONCLUSIONSMacrophages play a key role in clearing NETs from tissues. Endoplasmic reticulum stress suppresses macrophage DNase secretion, leading to NET accumulation in atherosclerotic plaques, which triggers efferocytosis impairment and plaque progression. Targeting the PERK-ATF4 axis to restore DNase release and NET clearance represents a promising therapeutic strategy to promote plaque stabilization.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"31 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194826","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":"GP130 Antagonism Enhances Porcine RV Function.","authors":"Jenna B Mendelson,Jacob D Sternbach,Minwoo Kim,Ryan A Moon,Lynn M Hartweck,Sophia R Clark,Walt Tollison,Matthew T Lahti,John P Carney,Todd Markowski,LeeAnn Higgins,Felipe Kazmirczak,Kurt W Prins","doi":"10.1161/circresaha.125.326336","DOIUrl":"https://doi.org/10.1161/circresaha.125.326336","url":null,"abstract":"BACKGROUNDRight ventricular (RV) dysfunction is a risk factor for death in multiple cardiovascular diseases, but RV-enhancing therapies are lacking. Inhibition of GP130 (glycoprotein-130) signaling with the small molecule SC144 improves RV function in rodent RV dysfunction via anti-inflammatory and metabolic mechanisms. However, SC144's efficacy and molecular effects in a translational large animal model of RV dysfunction are unknown.METHODSFour-week-old castrated male pigs underwent pulmonary artery banding (PAB). After 3 weeks, PAB pigs were randomized into 2 groups (daily injections of SC144 [2.2 mg/kg, PAB-SC144, n=5] or vehicle [PAB-Veh, n=5] for 3 weeks). Five age-matched pigs served as controls. Cardiac magnetic resonance imaging quantified RV size/function. Right heart catheterization evaluated hemodynamics. Single-nucleus RNA sequencing delineated cell-type-specific changes between experimental groups. Electron microscopy evaluated RV mitochondrial morphology. Phosphoproteomics identified dysregulated RV kinases. Lipidomics and metabolomics quantified lipid species and metabolites in RV tissue and serum. Quantitative proteomics examined RV mitochondrial protein regulation. Confocal microscopy evaluated alterations in cardiomyocyte size, macrophage abundances, capillary density, and pericyte/endothelial cell localization patterns.RESULTSSC144 significantly improved RV ejection fraction (control: 60±4%; PAB-Veh: 22±10%; PAB-SC144: 37±6%) without altering RV afterload. Single-nucleus RNA sequencing demonstrated that PAB-Veh pigs had lower cardiomyocyte and higher macrophage/lymphocyte/pericyte/endothelial cell abundances as compared with control, and many of these changes were blunted by SC144. Immunohistochemistry validated the reduction in RV macrophage infiltration by SC144. Both transcriptomics and proteomics approaches demonstrated that SC144 combatted the downregulation of cardiomyocyte metabolic genes/proteins induced by PAB. Kinome enrichment analysis suggested SC144 counteracted RV mTORC1 (mammalian target of rapamycin complex 1) activation. Correspondingly, SC144 rebalanced the RV autophagy pathway proteins and improved mitochondrial morphology. Integrated lipidomics, metabolomics, and proteomics analyses revealed that SC144 restored fatty acid metabolism. Finally, CellChat analysis, cardiomyocyte RNAseq analysis, and histological examination suggested SC144 rebalanced pericyte-endothelial cell interactions and blunted cardiomyocyte HIF1 (hypoxia-induced factor 1) activation.CONCLUSIONSGP130 antagonism blunts RV immune cell infiltration, reduces proinflammatory gene programs in macrophages and lymphocytes, rebalances autophagy, and preserves fatty acid metabolism in cardiomyocytes, and restores endothelial cell and pericyte homeostasis to mitigate cardiomyocyte hypoxia and ultimately augments RV function.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194878","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}