Nature cardiovascular research最新文献

{"title":"Ablating low-voltage areas does not suppress atrial fibrillation","authors":"Andrea Tavosanis","doi":"10.1038/s44161-025-00688-0","DOIUrl":"10.1038/s44161-025-00688-0","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"791-791"},"PeriodicalIF":10.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144546423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanosensitive PIEZO2 channels shape coronary artery development","authors":"Mireia Pampols-Perez, Carina Fürst, Oscar Sánchez-Carranza, Elena Cano, Jonathan Alexis Garcia-Contreras, Lisa Mais, Wenhan Luo, Sandra Raimundo, Eric L. Lindberg, Martin Taube, Arnd Heuser, Anje Sporbert, Dagmar Kainmueller, Miguel O. Bernabeu, Norbert Hübner, Holger Gerhardt, Gary R. Lewin, Annette Hammes","doi":"10.1038/s44161-025-00677-3","DOIUrl":"10.1038/s44161-025-00677-3","url":null,"abstract":"Coronary arteries develop under constant mechanical stress. However, the role of mechanosensitive ion channels in this process remains poorly understood. Here we show that the ion channel PIEZO2, which responds to mechanical stimuli, is expressed in specific coronary endothelial cell populations during a critical phase of coronary vasculature remodeling. These Piezo2+ coronary endothelial cells show distinct transcriptional profiles and have mechanically activated ionic currents. Strikingly, PIEZO2 loss-of-function mouse embryos and mice with human pathogenic variants of PIEZO2 show abnormal coronary vessel development and cardiac left ventricular hyperplasia. We conclude that an optimal balance of PIEZO2 channel function contributes to proper coronary vessel formation, structural integrity and remodeling, and is likely to support normal cardiac function. Our study highlights the importance of mechanical cues in cardiovascular development and suggests that defects in this mechanosensing pathway may contribute to congenital heart conditions. Pampols-Perez et al. identify the mechanosensitive ion channel PIEZO2 as a novel marker for embryonic coronary artery endothelial cells and as a critical regulator of coronary vascular remodeling. They show that in a distinct subset of coronary endothelial cells, PIEZO2 translates mechanically activated ionic currents into biological signals guiding coronary artery morphogenesis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"921-937"},"PeriodicalIF":10.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AIMP3 maintains cardiac homeostasis by regulating the editing activity of methionyl-tRNA synthetase","authors":"Anindhya S. Das, Charles P. Rabolli, Colton R. Martens, Han-Kai Jiang, Yingshen Zhang, Aubree A. Zimmer, Kevin Lin, Kedryn K. Baskin, Juan D. Alfonzo, Federica Accornero","doi":"10.1038/s44161-025-00670-w","DOIUrl":"10.1038/s44161-025-00670-w","url":null,"abstract":"In mammals, nine aminoacyl tRNA synthetases (ARSs) and three auxiliary proteins (ARS-interacting multifunctional proteins 1–3 (AIMP1–3)) form the multisynthetase complex (MSC), a molecular hub that provides a subset of aminoacylated tRNAs to the ribosome and partakes in translation-independent signaling. Knowledge of the role of AIMPs in organ physiology is currently limited. AIMP3 (also known as EEF1E1) was proposed to anchor methionyl tRNA synthetase (MetRS) in the complex and regulate protein synthesis through translation initiation and elongation. Here we show that a cardiomyocyte-specific conditional knockout of AIMP3 in mice leads to lethal cardiomyopathy. MetRS localization, aminoacylation efficiency and global protein synthesis were unaffected in our model, suggesting an alternative mechanism for the pathology. We found that AIMP3 is essential for homocysteine editing by MetRS, a reaction that is necessary for the maintenance of translation fidelity. Homocysteine accumulation induced reactive oxygen species production, protein aggregation, mitochondrial dysfunction, autophagy and ultimately cell death. Das et al. show that the correct editing activity of the methionyl tRNA synthetase, regulated by AIMP3, is required to prevent the accumulation of homocysteine and the resulting cardiomyocyte cell death and cardiac dysfunction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"876-890"},"PeriodicalIF":10.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144499774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maturation of human cardiac organoids enables complex disease modeling and drug discovery","authors":"Mark W. Pocock, Janice D. Reid, Harley R. Robinson, Natalie Charitakis, James R. Krycer, Simon R. Foster, Rebecca L. Fitzsimmons, Mary Lor, Lynn A. C. Devilée, Christopher A. P. Batho, Natasha Tuano, Sara E. Howden, Katerina Vlahos, Kevin I. Watt, Adam T. Piers, Kaitlyn Bibby, James W. McNamara, Rebecca Sutton, Valerii Iaprintsev, Jacob Mathew, Holly K. Voges, Patrick R. J. Fortuna, Sebastian Bass-Stringer, Celine Vivien, James Rae, Robert G. Parton, Anthony B. Firulli, Leszek Lisowski, Hannah Huckstep, Sean J. Humphrey, Sean Lal, Igor E. Konstantinov, Robert G. Weintraub, David A. Elliott, Mirana Ramialison, Enzo R. Porrello, Richard J. Mills, James E. Hudson","doi":"10.1038/s44161-025-00669-3","DOIUrl":"10.1038/s44161-025-00669-3","url":null,"abstract":"Maturation of human pluripotent stem (hPS) cell-derived cardiomyocytes is critical for their use as a model system. Here we mimic human heart maturation pathways in the setting of hPS cell-derived cardiac organoids (hCOs). Specifically, transient activation of 5′ AMP-activated protein kinase and estrogen-related receptor enhanced cardiomyocyte maturation, inducing expression of mature sarcomeric and oxidative phosphorylation proteins, and increasing metabolic capacity. hCOs generated using the directed maturation protocol (DM-hCOs) recapitulate cardiac drug responses and, when derived from calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) mutant hPS cells exhibit a pro-arrhythmia phenotype. These DM-hCOs also comprise multiple cell types, which we characterize and benchmark to the human heart. Modeling of cardiomyopathy caused by a desmoplakin (DSP) mutation resulted in fibrosis and cardiac dysfunction and led to identifying the bromodomain and extra-terminal inhibitor INCB054329 as a drug mitigating the desmoplakin-related functional defect. These findings establish DM-hCOs as a versatile platform for applications in cardiac biology, disease and drug screening. Pocock et al. reveal that transient activation of 5′ AMP-activated protein kinase and estrogen-related receptor drives robust maturation of multicellular human cardiac organoids, enabling modeling of desmoplakin cardiomyopathy dysfunction, which could be rescued using the bromodomain and extra-terminal inhibitor INCB054329.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"821-840"},"PeriodicalIF":10.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144499775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of effector Treg signature in APOB-reactive CD4+ T cells in patients with coronary artery disease","authors":"Payel Roy, Anusha Bellapu, Sujit Silas Armstrong Suthahar, Mohammad Oliaeimotlagh, Qingkang Lyu, Smriti Parashar, Jeffrey Makings, Runpei Wu, Sunil Kumar, Megh Mehta, Austin W. T. Chiang, Alessandro Sette, Coleen A. McNamara, Klaus Ley","doi":"10.1038/s44161-025-00671-9","DOIUrl":"10.1038/s44161-025-00671-9","url":null,"abstract":"Atherosclerosis underlies most coronary artery disease (CAD). It involves a significant autoimmune component against apolipoprotein B (APOB). In this study, we used short activation-induced marker (AIM) assays to characterize APOB-reactive CD4+ T cells in patients with angiographically verified CAD. APOB-reactive CD4+ T cells expressing CD25 and 4-1BB markers were the most abundant. Their frequency correlated positively with CAD severity. Transcriptomic analysis revealed that these cells were clonally expanded and significantly enriched in genes expressed in tissue-homing effector regulatory T (eTreg) cells. They shared signatures with CD4+ T cells in mouse and human plaques, including expression of the plaque-homing chemokine receptor CXCR6. With increasing disease severity, the Treg signature was progressively and significantly lost. Conversely, APOB-specific Treg cells from patients with severe CAD gained glycolytic and interferon response signatures. We conclude that mild CAD is associated with a regulatory program in APOB-reactive CD4+ T cells, which is replaced by a pro-inflammatory program in patients with severe CAD. By characterizing APOB-reactive CD4+ T cells in patients with atherosclerosis, Roy et al. identify effector regulatory T (eTreg) cells as the predominant autoreactive subset. These APOB-specific eTreg cells are clonally expanded, express the plaque-homing receptor CXCR6 and progressively lose their regulatory phenotype as disease severity increases.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"841-856"},"PeriodicalIF":10.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pioneer transcription factor two-pronged way to promote endothelial cell differentiation","authors":"","doi":"10.1038/s44161-025-00661-x","DOIUrl":"10.1038/s44161-025-00661-x","url":null,"abstract":"Single-cell analyses defined the mechanisms by which the pioneer transcription factor ETV2 drives endothelial cell specification from mesodermal progenitors in vitro. ETV2 interaction with a transcription factor (GABPA) promoted endothelial cells differentiation, and ETV2 interaction with a repressor (REST) inhibited differentiation to alternative cell types.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 6","pages":"657-658"},"PeriodicalIF":10.8,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A tunable gene therapy for heart regeneration","authors":"Gabriele D’Uva","doi":"10.1038/s44161-025-00666-6","DOIUrl":"10.1038/s44161-025-00666-6","url":null,"abstract":"AAV-based gene therapies hold promise for treating disease, but their long-lasting gene expression limits their use in regenerative medicine. A study now presents DreAM, a drug-inducible AAV system that enables tunable tissue-specific gene activation via the splicing modulator risdiplam, and its potential application in myocardial infarction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"794-796"},"PeriodicalIF":10.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The drug-elicitable alternative splicing module for tunable vector expression in the heart","authors":"Zhan Chen, Luzi Yang, Yueyang Zhang, Jiting Li, Yuhan Yang, Yue Li, Linwei Fan, Wei Chen, Lei Miao, Jin Liu, Gonglie Chen, Ze Wang, Yifei Li, Fei Gao, Jing Zhou, Lemin Zheng, Yan Zhang, Dongyu Zhao, William T. Pu, Ke Yang, Erdan Dong, Yuxuan Guo","doi":"10.1038/s44161-025-00665-7","DOIUrl":"10.1038/s44161-025-00665-7","url":null,"abstract":"Adeno-associated viruses (AAVs) are commonly used for gene therapy, but a clinically relevant method to fine-tune AAV expression is lacking, restricting their therapeutic efficacy and safety. Here we develop the drug-elicitable alternative splicing module (DreAM), which is responsive to risdiplam, a Food and Drug Administration-approved alternative splicing modulator. Risdiplam activated DreAM-regulated AAV expression in a dose-dependent manner with a 2,000-fold inducible change, depending on the dose of risdiplam and the organ of interest. With a temporal resolution of 2 days, DreAM could transiently, reversibly and repeatedly activate AAV expression according to the frequency and duration of risdiplam administration. In this proof-of-concept study, we incorporated DreAM into the cardiomyocyte-specific, liver-detargeted AAV9-Tnnt2-miR122TS vector to transiently activate the cardiomyocyte regeneration factor YAP5SA. A dedifferentiation–proliferation–redifferentiation cycle was established in adult cardiomyocytes, improving cardiac regeneration after myocardial infarction while limiting animal death, AAV9-Tnnt2 expression in the liver and hepatic tumorigenesis. Therefore, DreAM may enhance the efficacy, safety and scope of gene therapy. Chen, Yang et al. present DreAM, the drug-elicitable alternative splicing module, which is responsive to risdiplam, to inducibly regulate adeno-associated virus vector-mediated transgene expression. Proof-of-concept applications in cardiomyocytes revealed its potential for future clinical use in improving cardiac recovery after myocardial infarction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 7","pages":"938-955"},"PeriodicalIF":10.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secondary analysis of the EMPACT-MI trial reveals cardiovascular–kidney efficacy and safety of empagliflozin after acute myocardial infarction","authors":"Rahul Aggarwal, Deepak L. Bhatt, Adrian F. Hernandez, Stefan D. Anker, Josephine Harrington, W. Schuyler Jones, Michaela Mattheus, Mark C. Petrie, Dominik Steubl, Mikhail Sumin, Vikram Thanam, Jacob A. Udell, Javed Butler","doi":"10.1038/s44161-025-00657-7","DOIUrl":"10.1038/s44161-025-00657-7","url":null,"abstract":"Data on the cardiovascular–kidney effects and safety of empagliflozin among patients with acute myocardial infarction are limited. EMPACT-MI (Study to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) was a double-blind, multicenter clinical trial that randomized 6,522 patients with acute myocardial infarction and risk for heart failure to empagliflozin or placebo. Here we show in this secondary analysis that the mean estimated glomerular filtration rate at baseline was 76.1 ml min−1 1.73 m−2 (s.d. = 19.9 ml min−1 1.73 m−2), with longitudinal kidney function data available for 1,152 (17.7%) treated patients from select countries. By 24 months, compared with baseline, the estimated glomerular filtration rate was similar in the empagliflozin group but declined in the placebo group (P = 0.01). Empagliflozin reduced the total adverse events of heart failure or all-cause mortality irrespective of kidney function (Pinteraction = 0.30). Thirty-day adverse event rates were similar by treatment group and consistent across baseline kidney function. Empagliflozin had kidney-protective effects, reduced heart failure outcomes and was safe to initiate soon after acute myocardial infarction across baseline kidney function. Aggarwal et al. report a secondary analysis of the EMPACT-MI trial, which evaluates the effects of empagliflozin according to baseline kidney function in patients after myocardial infarction, showing that empagliflozin offers kidney protection, reduces heart failure events and was safe to initiate in patients with acute myocardial infarction, irrespective of baseline kidney function.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 6","pages":"761-772"},"PeriodicalIF":10.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reversal of cerebrovascular anomalies in a zebrafish model of vein of Galen aneurysm","authors":"Edwige Martin-Valiente, Yao Du, Chloé Goemans, Michelle America, Egor Zindy, Myckel Adam, Benoit Scheid, Miikka Vikkula, Boris Lubicz, Benoit Vanhollebeke, Nicolas Baeyens","doi":"10.1038/s44161-025-00659-5","DOIUrl":"10.1038/s44161-025-00659-5","url":null,"abstract":"Congenital vascular malformations result from abnormal development of the vascular tree, with the aneurysmal malformation of the vein of Galen (VGAM) being the most prevalent neurovascular malformation in neonates, associated with poor outcomes. This condition is linked to germline mutations in the RASA1 and EPHB4 genes, although the underlying developmental mechanisms remain unclear. Here we generate zebrafish models lacking rasa1a and ephb4a that replicate the genetic and structural features of VGAMs. Our findings connect the development of malformations to insufficient fusion of precursor blood vessels, a process regulated by blood flow and the responses of endothelial cells. RASA1 deficiency destabilizes the homeostatic response to blood flow and contributes to impaired flow-mediated activation of MAPK and phosphatidylinositol-3-kinase signaling. By pharmacologically targeting these signaling pathways in mutant models, we restore normal fusion in existing malformations, offering potential new strategies for treating VGAMs and similar vascular remodeling disorders. Martin-Valiente, Du et al. generate a zebrafish model of vein of Galen aneurysm, reproducing the disease’s structural features and revealing its developmental origin. By pharmacologically targeting MAPK and PI3K signaling pathways in mutant models, they restore normal fusion of precursor blood vessels in existing malformations.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 6","pages":"773-789"},"PeriodicalIF":10.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}