Cardiovascular Research最新文献

{"title":"Redirecting full-length FLT1 expression towards its soluble isoform by targeting alternative polyadenylation promotes postischaemic angiogenesis","authors":"Maja Bundalo,Sandra Vorlova,Jessica Ulrich,Giuseppe Rizzo,Elke Butt,Hendrik Bartolomaeus,Hla Ali,Ruggero Barbieri,Leon Richter,Leonie Höna,Manuel Egg,Julian Bock,Sarah Schäfer,Núria Amézaga Solé,Annabelle Rosa,Clément Cochain,Andreas Beilhack,Wolfgang Kastenmüller,Erik Henke,Boris V Skryabin,Timofey S Rozhdestvensky,Moritz Wildgruber,Kari Alitalo,Kristina Lorenz,Michaela Kuhn,Alma Zernecke","doi":"10.1093/cvr/cvag198","DOIUrl":"https://doi.org/10.1093/cvr/cvag198","url":null,"abstract":"Abstract Aims Vascular endothelial growth factors (VEGFs) and their endothelial tyrosine kinase receptors are crucial mediators of vasculogenesis and angiogenesis, with FLT1 (VEGFR1) acting as a decoy receptor for VEGFs. Alternative polyadenylation (APA) of Flt1 transcripts produces a truncated mRNA transcript encoding soluble (s) FLT1, which contains only the extracellular ligand-binding domain. The relative roles of full-length (fl) FLT1 and sFLT1 in angiogenesis are incompletely understood. Alternative polyadenylation is an important post-transcriptional mechanism of gene regulation that is increasingly recognized to affect the expression of many genes related to cardiovascular diseases. However, there are no in vivo models available to target APA and to examine the physiological roles of gene isoforms. Methods and results We here generated mice by introducing silent mutations into the Flt1 exon 13/intron 13 5′ splice site through homology-directed repair with CRISPR/Cas9 gene editing. Embryonic development, postnatal retinal vascular development, and reparative angiogenesis were evaluated in models of hindlimb ischaemia and myocardial infarction, complemented by assessments of cardiac functional recovery and cell phenotypes through snRNAseq, as well as in vitro assays examining endothelial cell phenotype and function. The introduction of specific splice site mutations within Flt1 to activate APA led to a complete loss of flFLT1 and an increase in sFLT1 expression. Using this mouse model, we demonstrate that sFLT1 alone is sufficient for developmental vasculogenesis, whereas the specific loss of flFLT1 enhances reparative revascularization and angiogenesis and improves cardiac recovery after myocardial infarction. Conclusion Our findings show that APA can be effectively targeted to modulate FLT1 isoform expression in vivo. Our mouse model may help to understand diseases driven by an imbalance in FLT1 isoform expression. Given the widespread presence of APA signals, our approach could furthermore serve as a model for studying the function of other truncated gene isoforms.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"404 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087905","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":"PlGF in pulmonary hypertension: addressing the angiogenesis paradox via immune remodeling","authors":"Qingqing Meng,Stephen Y Chan","doi":"10.1093/cvr/cvag224","DOIUrl":"https://doi.org/10.1093/cvr/cvag224","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"1 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087906","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":"A shift in the platelet lipidome correlates with platelet differentiation into distinct subfractions in patients with pulmonary embolism","authors":"Jessica Kristin Henes,Tobias Harm,Manuel Friedel,Rebecca Stübenrath,Zoi Laspa,David Schaale,Valerie Dicenta-Baunach,Anne-Katrin Rohlfing,Karin Müller,Michal Droppa,Zijing Xu,Xiaoqing Fu,Tobias Geisler,Michael Laemmerhofer,Meinrad Gawaz,Dominik Rath","doi":"10.1093/cvr/cvag188","DOIUrl":"https://doi.org/10.1093/cvr/cvag188","url":null,"abstract":"Abstract Aims Severity of pulmonary embolism (PE) is significantly driven by right ventricular (RV) failure and thrombus composition, which possibly alters susceptibility towards therapy. Following platelet activation, platelets differentiate into different phenotypes, including a procoagulant and an aggregatory phenotype. Differentiation into these phenotypes is associated with changes in the platelet lipidome. Hence, we sought to investigate platelet subpopulations and the platelet lipidome in patients with acute PE and concomitant vs. absent RV distress. Methods and results We examined isolated platelets from 48 patients with acute PE. PE and RV distress were diagnosed with CT pulmonary angiogram (CTPA) and transthoracic echocardiography, respectively. We identified platelet subpopulations based on platelet surface exposure of CD42b, phosphatidylserine and GPIIb/IIIa using flow cytometry. Additionally, the platelet lipidome was characterized via HPLC-ESI-QTOF-MS/MS. In patients with RV distress, we found higher levels of aggregatory (P = 0.021) and lower levels of procoagulant platelets (P = 0.033) when compared with patients without RV dysfunction. Moreover, we found a significant upregulation of cholesteryl esters, triglycerides and fatty acyls in platelets of PE patients with RV dysfunction compared to PE patients with normal RV. Finally, a significant correlation of lipids with levels of aggregatory and procoagulant platelets was observed in the overall cohort of patients. Conclusion Specific stimuli can activate distinct metabolic programmes, leading to remodelling of the platelet lipidome that may influence the differentiation of platelets into separate phenotypic subpopulations in PE.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"24 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087985","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":"Comorbidity-specific molecular programmes of early diastolic dysfunction identify glucocorticoid receptor activation as a causal driver in obesity.","authors":"Antonella Ausiello, Laura Lalaguna, Marina López-Olañeta, Carlos Torroja, Julia Palacios-Merino, Carlos G Sánchez-Cabezudo, Patricia Rivas, María Villalba-Orero, Elena Fernández-Cortés, Pablo García-Pavía, María Victoria Gómez-Gaviro, Domingo Pascual-Figal, Enrique Lara-Pezzi","doi":"10.1093/cvr/cvag193","DOIUrl":"https://doi.org/10.1093/cvr/cvag193","url":null,"abstract":"<p><strong>Aims: </strong>Early diastolic dysfunction precedes the development of HFpEF, but the molecular events that initiate this process remain poorly defined. HFpEF arises in the setting of systemic comorbidities such as obesity (OB), hypertension, hyperglycaemia (HG), and sleep apnoea, which often coexist and make it difficult to distinguish their individual contributions to early cardiac remodelling. Here, we aimed to define the early, comorbidity-specific mechanisms that initiate diastolic dysfunction across major HFpEF-associated conditions.</p><p><strong>Methods and results: </strong>We performed single-nucleus RNA sequencing (snRNA-seq) of left ventricles from mouse models of OB, systemic arterial hypertension (SAH), chronic intermittent hypoxia (CIH), and HG at the time point corresponding to early diastolic impairment. Findings were validated by qRT-PCR, immunohistochemistry, and targeted interventions.OB and HG induced the most extensive transcriptional remodelling, affecting cardiomyocytes, fibroblasts, endothelial cells, and macrophages, while SAH and CIH produced comparatively more modest changes. Cardiomyocytes developed comorbidity-specific stress programmes, with glucocorticoid receptor (GR)-driven activation in OB, combined FoxO and GR signalling in HG, mitochondrial and sarcomeric remodelling in hypertension, and minimal changes in hypoxia. Fibroblasts and endothelial cells in OB and HG mice adopted profibrotic and angiogenesis-impaired profiles, and macrophages polarized towards GR-regulated or immunomodulatory states, depending on the comorbidity. Correction of OB at mid-life improved ventricular relaxation, delayed HFpEF onset, and reduced GR target expression. Direct GR inhibition through overexpression of the lncRNA GAS5 or with mifepristone treatment rescued diastolic function independently of weight loss. In HG mice, CnAβ1 overexpression reduced baseline expression of FoxO target genes, corrected atrophy, but did not prevent FoxO target induction under HG or restore relaxation.</p><p><strong>Conclusion: </strong>Early diastolic dysfunction arises through comorbidity-specific molecular programmes. OB-induced GR activation emerges as a causal and actionable driver of diastolic dysfunction. These findings provide mechanistic insight into comorbidity-specific pathways in HFpEF and support the development of stratified therapeutic approaches.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079950","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":"Age-related changes in spermidine and association with incident heart failure.","authors":"Andrew I Lyon, Carl Lejonberg, Ulrika Ericson, Tomasz Czuba, Mahmoud Abdellatif, Jakub Morze, Olle Melander, Kristina Sundquist, Clemens Wittenbecher, Simon Sedej, Malin Levin, Marju Orho-Melander, Gunnar Engström, Olof Gidlöf, J Gustav Smith","doi":"10.1093/cvr/cvag221","DOIUrl":"https://doi.org/10.1093/cvr/cvag221","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079992","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":"The unforeseen twist of Sirt1 in cardiac hypertrophy.","authors":"Tarik Bozoglu, Vijjayanand Rajendran, Julian Grünewald, Christian Kupatt","doi":"10.1093/cvr/cvag218","DOIUrl":"https://doi.org/10.1093/cvr/cvag218","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069249","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":"Do we know the wizard: emerging roles of nexus glia in peripheral physiology","authors":"Ondrea S Amandhi Mathews,Sarah Shibuya,Cody J Smith","doi":"10.1093/cvr/cvag219","DOIUrl":"https://doi.org/10.1093/cvr/cvag219","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"13 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049129","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":"Spatial APD heterogeneity: new insights into the role of sinus activation time.","authors":"Miriam Barbieri, Katja E Odening","doi":"10.1093/cvr/cvag216","DOIUrl":"https://doi.org/10.1093/cvr/cvag216","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036555","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":"Timing of food intake impacts cardiovascular and neuroendocrine physiology and risk of disease.","authors":"Mary N Latimer, Megan K Rhoads, David M Pollock","doi":"10.1093/cvr/cvag169","DOIUrl":"10.1093/cvr/cvag169","url":null,"abstract":"<p><p>Despite many advances in the last 75 years in the fight against cardiovascular disease mortality, it remains the leading cause of death worldwide. Despite improved therapeutic approaches, cardiovascular disease remains the leading cause of death worldwide. Mounting evidence suggests that restricting food intake to a limited period in the day or extending periods of fasting may be a lifestyle intervention that reduces progression of cardiovascular disease. Various protocols for time-restricted feeding paradigms suggest significant benefits throughout the cardiovascular system. Despite some limitations to their use, the general mechanism is thought to revolve around circadian alignment of cellular and organ function with behavioural and environmental patterns. Here, we review recent evidence in a rapidly expanding field that strives to understand how timing of food intake regulates circadian physiology of cardiovascular systems focusing on heart, vascular, and neuroendocrine physiology. We review both pre-clinical and clinical reports showing how timed feeding may alter organ function in both health and disease.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1740-1760"},"PeriodicalIF":12.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711522","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":"A distinct T-cell receptor signature associates with cardiac outcome in myocardial infarction patients.","authors":"Kenz Le Gouge, DiyaaElDin Ashour, Margarete Heinrichs, Paul Stys, Pierre Barennes, Verena Stangl, Lavinia Rech, Gerald Hoefler, Karl Kashofer, Tobias Gassenmaier, Valerie Boivin-Jahns, Roland Jahns, Andreas Zirlik, Ulrich Hofmann, Dominik Schmitt, Anna Frey, Stefan Störk, Stefan Frantz, Peter P Rainer, Gustavo Campos Ramos, Encarnita Mariotti-Ferrandiz","doi":"10.1093/cvr/cvag162","DOIUrl":"10.1093/cvr/cvag162","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1736-1739"},"PeriodicalIF":12.5,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148599331","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}