Cardiovascular Research最新文献

{"title":"Oxidative DNA damage promotes vascular ageing associated with changes in extracellular matrix-regulating proteins.","authors":"Kirsty Foote, Marieke Rienks, Lukas Schmidt, Konstantinos Theofilatos, Yasmin, Matiss Ozols, Alexander Eckersley, Aarti Shah, Nichola Figg, Alison Finigan, Kevin O'Shaughnessy, Ian Wilkinson, Manuel Mayr, Martin Bennett","doi":"10.1093/cvr/cvae091","DOIUrl":"10.1093/cvr/cvae091","url":null,"abstract":"<p><strong>Aims: </strong>Vascular ageing is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular ageing, but how it regulates ECM proteins and vascular stiffening is unknown. We sought to determine the relationship between oxidative DNA damage and ECM regulatory proteins in vascular ageing.</p><p><strong>Methods and results: </strong>We examined oxidative DNA damage, the major base excision repair (BER) enzyme 8-Oxoguanine DNA Glycosylase (Ogg1) and its regulators, multiple physiological markers of ageing, and ECM proteomics in mice from 22 to 72 w. Vascular ageing was associated with increased oxidative DNA damage, and decreased expression of Ogg1, its active acetylated form, its acetylation regulatory proteins P300 and CBP, and the transcription factor Foxo3a. Vascular stiffness was examined in vivo in control, Ogg1-/-, or mice with vascular smooth muscle cell-specific expression of Ogg1+ (Ogg1) or an inactive mutation (Ogg1KR). Ogg1-/- and Ogg1KR mice showed reduced arterial compliance and distensibility, and increased stiffness and pulse pressure, whereas Ogg1 expression normalized all parameters to 72 w. ECM proteomics identified major changes in collagens with ageing, and downregulation of the ECM regulatory proteins Protein 6-lysyl oxidase (LOX) and WNT1-inducible-signaling pathway protein 2 (WISP2). Ogg1 overexpression upregulated LOX and WISP2 both in vitro and in vivo, and downregulated Transforming growth factor β1 (TGFb1) and Collagen 4α1 in vivo compared with Ogg1KR. Foxo3a activation induced Lox, while Wnt3 induction of Wisp2 also upregulated LOX and Foxo3a, and downregulated TGFβ1 and fibronectin 1. In humans, 8-oxo-G increased with vascular stiffness, while active OGG1 reduced with both age and stiffness.</p><p><strong>Conclusion: </strong>Vascular ageing is associated with oxidative DNA damage, downregulation of major BER proteins, and changes in multiple ECM structural and regulatory proteins. Ogg1 protects against vascular ageing, associated with changes in ECM regulatory proteins including LOX and WISP2.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"614-628"},"PeriodicalIF":10.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140875943","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":"Antisense-mediated regulation of exon usage in the elastic spring region of Titin modulates sarcomere function.","authors":"Selvi Celik, Ludvig Hyrefelt, Tomasz Czuba, Yuan Li, Juliana Assis, Julia Martinez, Markus Johansson, Oscar André, Jane Synnergren, Joakim Sandstedt, Pontus Nordenfelt, Kristina Vukusic, J Gustav Smith, Olof Gidlöf","doi":"10.1093/cvr/cvaf037","DOIUrl":"10.1093/cvr/cvaf037","url":null,"abstract":"<p><strong>Aims: </strong>Alternative splicing of Titin (TTN) I-band exons produce protein isoforms with variable size and elasticity, but the mechanisms whereby TTN splice factors regulate exon usage and thereby determining cardiomyocyte passive stiffness and diastolic function, is not well understood. Non-coding RNA transcripts from the antisense strand of protein-coding genes have been shown to regulate alternative splicing of the sense gene. The TTN gene locus harbours >80 natural antisense transcripts (NATs) with unknown function in the human heart. The aim of this study was to determine if TTN antisense transcripts play a role in alternative splicing of TTN.</p><p><strong>Methods and results: </strong>RNA-sequencing and RNA in situ hybridization (ISH) of cardiac tissue from heart failure (HF) patients, unused donor hearts, and human iPS-derived cardiomyocytes (iPS-CMs) were used to determine the expression and localization of TTN NATs. Live cell imaging was used to analyse the effect of NATs on sarcomere properties. RNA ISH and immunofluorescence was performed in iPS-CMs to study the interaction between NATs, TTN mRNA, and splice factor protein RBM20. We found that TTN-AS1-276 was the predominant TTN NAT in the human heart and that it was up-regulated in HF. Knockdown of TTN-AS1-276 in human iPS-CMs resulted in decreased interaction between RBM20 and TTN pre-mRNA, decreased TTN I-band exon skipping, and markedly lower expression of the less compliant TTN isoform N2B. The effect on TTN exon usage was independent of sense-antisense exon overlap and polymerase II elongation rate. Furthermore, knockdown resulted in longer sarcomeres with preserved alignment, improved fractional shortening, and relaxation times.</p><p><strong>Conclusions: </strong>We demonstrate a role for TTN-AS1-276 in facilitating alternative splicing of TTN and regulating sarcomere properties. This transcript could constitute a target for improving cardiac passive stiffness and diastolic function in conditions such as heart failure with preserved ejection fraction.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"629-642"},"PeriodicalIF":10.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555986","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":"Plasma proteomic and metabolomic profiling of coronary and carotid atherosclerosis in the SCAPIS study - differences and similarities.","authors":"Tove Fall,Anders Gummesson,Ulf Hammar,Håkan Ahlström,Oskar Angerås,Anders Blomberg,John Brandberg,Kenneth Caidahl,Elin Chorell,Jan E Engvall,Per Eriksson,David Erlinge,Bruna Gigante,Ola Hjelmgren,Johan Hultdin,Tomas Jernberg,Johan Kihlberg,Lars Lind,Martin Magnusson,Fredrik H Nyström,Carlo Pirazzi,Alexandru Schiopu,Johan Sundström,Stefan Söderberg,Carl Johan Östgren,Gunnar Engström","doi":"10.1093/cvr/cvaf076","DOIUrl":"https://doi.org/10.1093/cvr/cvaf076","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"13 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915031","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":"Harnessing the power of the brain to fight metabolic diseases.","authors":"Emiel P C van der Vorst,Giuseppe Lembo","doi":"10.1093/cvr/cvaf061","DOIUrl":"https://doi.org/10.1093/cvr/cvaf061","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"115 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914868","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":"Novel role of vascular smooth muscle cell-expressed METTL3 in atherosclerosis.","authors":"Joanna Stuck, Islam Osman","doi":"10.1093/cvr/cvaf036","DOIUrl":"10.1093/cvr/cvaf036","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"526-527"},"PeriodicalIF":10.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555988","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":"Unveiling the role of tyrosine kinases in doxorubicin-induced cardiotoxicity and beyond.","authors":"Edoardo Lazzarini, Claudia Altomare, Lucio Barile","doi":"10.1093/cvr/cvaf035","DOIUrl":"10.1093/cvr/cvaf035","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"530-531"},"PeriodicalIF":10.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623594","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 SORBS2 expression increases in heart failure and regulates integrin interactions and extracellular matrix composition.","authors":"Louk T Timmer, Elvira den Hertog, Danielle Versteeg, Harm Post, Job A J Verdonschot, Jantine Monshouwer-Kloots, Eirini Kyriakopoulou, Ilaria Perini, Tim Koopmans, Petra van der Kraak, Lorena Zentilin, Stephane R B Heymans, Aryan Vink, Mauro Giacca, Albert J R Heck, Eva van Rooij","doi":"10.1093/cvr/cvaf021","DOIUrl":"10.1093/cvr/cvaf021","url":null,"abstract":"<p><strong>Aims: </strong>In this study, we aimed to uncover genes associated with stressed cardiomyocytes by combining single-cell transcriptomic data sets from failing cardiac tissue from both humans and mice.</p><p><strong>Methods and results: </strong>Our bioinformatic analysis identified SORBS2 as conserved NPPA-correlated gene. Using mouse models and cardiac tissue from human heart failure patients, we demonstrated that SORBS2 expression is consistently increased during pathological remodelling, correlates to disease severity, and is regulated by GATA4. By affinity purification mass spectrometry, we showed SORBS2 to interact with the integrin-cytoskeleton connections. Cardiomyocyte-specific genetic loss of Sorbs2 in adult mice changed integrin interactions, indicated by the increased expression of several integrins and altered extracellular matrix components connecting to these integrins, leading to an exacerbated fibrotic response during pathological remodelling.</p><p><strong>Conclusion: </strong>Sorbs2 is a cardiomyocyte-enriched gene that is increased during progression to heart failure in a GATA4-dependent manner and correlates to phenotypical hallmarks of cardiac failure. Our data indicate SORBS2 to function as a crucial regulator of integrin interactions and cardiac fibrosis.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"585-600"},"PeriodicalIF":10.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432546","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":"Advancing cardiovascular risk assessment.","authors":"Christos P Kotanidis, Brittany Weber","doi":"10.1093/cvr/cvae234","DOIUrl":"10.1093/cvr/cvae234","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"523-525"},"PeriodicalIF":10.2,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615576","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":"The three calmodulin genes - territories defined?","authors":"Marcos Gonzalez,Quang-Kim Tran","doi":"10.1093/cvr/cvaf075","DOIUrl":"https://doi.org/10.1093/cvr/cvaf075","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"23 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143903086","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":"Glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist tirzepatide promotes branched chain amino acid catabolism to prevent myocardial infarction in non-diabetic mice.","authors":"Mengya Chen, Nan Zhao, Wenke Shi, Yun Xing, Shiqiang Liu, Xianxian Meng, Lanlan Li, Heng Zhang, Yanyan Meng, Saiyang Xie, Wei Deng","doi":"10.1093/cvr/cvaf005","DOIUrl":"10.1093/cvr/cvaf005","url":null,"abstract":"<p><strong>Aims: </strong>A novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, tirzepatide (LY3298176, TZP), has been developed to treat Type 2 diabetes mellitus (T2DM). In ischaemic heart diseases, TZP is involved in cardiac metabolic processes. However, its efficacy and safety in treating heart failure (HF) following myocardial infarction (MI) remain uncertain.</p><p><strong>Methods and results: </strong>Herein, 12 week C57BL/6J mice were subjected to MI surgery, followed by administration of TZP. The effects of TZP on cardiac function and metabolism were thoroughly assessed by physiological, histological, and cellular analyses. Downstream effectors of TZP were screened through untargeted metabolomics analysis and molecular docking. Construct a lower branched chain amino acid (BCAA) diet model to determine whether TZP's cardioprotective effect is associated with reducing BCAA levels. Our results demonstrated that TZP reduced mortality following MI, decreased the infarct area, and attenuated cardiomyocyte necrosis. Pathological evaluation of cardiac tissues demonstrated increased fibrosis repair and decreased inflammatory infiltration. Mechanistically, untargeted metabolomics analysis uncovered a positive correlation between TZP and the BCAA catabolism pathway. The molecular docking verified that TZP could bind with branched-chain keto acid dehydrogenase E1 subunit α (BCKDHA). TZP reduced BCKDHA phosphorylation at S293, enhanced BCAA catabolism, and inhibited the activation of metabolism by activating rapamycin (mTOR) signalling pathway. Furthermore, mice fed a low-BCAA diet post-MI demonstrated reduced cardiomyocyte necrosis, increased fibrosis repair, and decreased inflammatory infiltration. These cardioprotective effects were further enhanced when used synergistically with TZP.</p><p><strong>Conclusion: </strong>Taken together, our findings provide new perspectives on the unrecognized role of TZP in cardiac protection. TZP enhanced BCAA catabolism and attenuated BCAA/mTOR signalling pathway in MI mice. Consequently, this study may present novel therapeutic options for patients with HF.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"454-467"},"PeriodicalIF":10.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390382","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}