Cardiovascular Research最新文献

{"title":"Smooth muscle-specific deletion of cellular communication network factor 2 causes severe aorta malformation and atherosclerosis.","authors":"Jannik H Larsen, Julie S Hegelund, Matilde K Pedersen, Cecilie M Andersson, Caroline A Lindegaard, Didde R Hansen, Jane Stubbe, Jes S Lindholt, Camilla S Hansen, Andrietta Grentzmann, Maria Bloksgaard, Boye L Jensen, Raúl R Rodriguez-Díez, Marta Ruiz-Ortega, Sebastian Albinsson, Gerard Pasterkamp, Michal Mokry, Andrew Leask, Roel Goldschmeding, Bartosz Pilecki, Grith L Sorensen, Charles Pyke, Martin Overgaard, Hans C Beck, Daniel F J Ketelhuth, Lars M Rasmussen, Lasse B Steffensen","doi":"10.1093/cvr/cvae174","DOIUrl":"10.1093/cvr/cvae174","url":null,"abstract":"<p><strong>Aims: </strong>Cellular communication network factor 2 (CCN2) is a matricellular protein implicated in fibrotic diseases, with ongoing clinical trials evaluating anti-CCN2-based therapies. By uncovering CCN2 as abundantly expressed in non-diseased artery tissue, this study aimed to investigate the hypothesis that CCN2 plays a pivotal role in maintaining smooth muscle cell (SMC) phenotype and protection against atherosclerosis.</p><p><strong>Methods and results: </strong>Global- and SMC-specific Ccn2 knockout mouse models were employed to demonstrate that Ccn2 deficiency leads to SMC de-differentiation, medial thickening, and aorta elongation under normolipidaemic conditions. Inducing hyperlipidaemia in both models resulted in severe aorta malformation and a 17-fold increase in atherosclerosis formation. Lipid-rich lesions developed at sites of the vasculature typically protected from atherosclerosis development by laminar blood flow, covering 90% of aortas and extending to other vessels, including coronary arteries. Evaluation at earlier time points revealed medial lipid accumulation as a lesion-initiating event. Fluorescently labelled LDL injection followed by confocal microscopy showed increased LDL retention in the medial layer of Ccn2 knockout aortas, likely attributed to marked proteoglycan enrichment of the medial extracellular matrix. Analyses leveraging data from the Athero-Express study cohort indicated the relevance of CCN2 in established human lesions, as CCN2 correlated with SMC marker transcripts across 654 transcriptomically profiled carotid plaques. These findings were substantiated through in situ hybridization showing CCN2 expression predominantly in the fibrous cap.</p><p><strong>Conclusion: </strong>This study identifies CCN2 as a major constituent of the normal artery wall, critical in regulating SMC differentiation and aorta integrity and possessing a protective role against atherosclerosis development. These findings underscore the need for further investigation into the potential effects of anti-CCN2-based therapies on the vasculature.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1851-1868"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016474","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":"Modulation of MMP9 and CXCR2/CXCL1/IL-8 axis in human abdominal aortic aneurysm tissues by ladarixin.","authors":"Maria Lombardi, Lucia Spartano, Sabrina Nicolo, Vincenzo Ardita, Roberto Chiesa, Andrea Aramini, Marcello Allegretti, Domenico Baccellieri, Lidia De Filippis, Chiara Foglieni","doi":"10.1093/cvr/cvae179","DOIUrl":"10.1093/cvr/cvae179","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1832-1834"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139418","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 diabetic myocardial transcriptome reveals Erbb3 and Hspa2 as a novel biomarkers of incident heart failure.","authors":"Marcella S Conning-Rowland, Marilena Giannoudi, Michael Drozd, Oliver I Brown, Nadira Y Yuldasheva, Chew W Cheng, Paul J Meakin, Sam Straw, John Gierula, Ramzi A Ajjan, Mark T Kearney, Eylem Levelt, Lee D Roberts, Kathryn J Griffin, Richard M Cubbon","doi":"10.1093/cvr/cvae181","DOIUrl":"10.1093/cvr/cvae181","url":null,"abstract":"<p><strong>Aims: </strong>Diabetes mellitus (DM) increases heart failure incidence and worsens prognosis, but its molecular basis is poorly defined in humans. We aimed to define the diabetic myocardial transcriptome and validate hits in their circulating protein form to define disease mechanisms and biomarkers.</p><p><strong>Methods and results: </strong>RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project was used to define differentially expressed genes (DEGs) in right atrial (RA) and left ventricular (LV) myocardium from people with vs. without DM (type 1 or 2). DEGs were validated as plasma proteins in the UK Biobank cohort, searching for directionally concordant differential expression. Validated plasma proteins were characterized in UK Biobank participants, irrespective of diabetes status, using cardiac magnetic resonance imaging, incident heart failure, and cardiovascular mortality. We found 32 and 32 DEGs associated with DM in the RA and LV, respectively, with no overlap between these. Plasma proteomic data were available for 12, with ERBB3, NRXN3, and HSPA2 (all LV hits) exhibiting directional concordance. Irrespective of DM status, lower circulating ERBB3 and higher HSPA2 were associated with impaired LV contractility and higher LV mass. Participants in the lowest quartile of circulating ERBB3 or highest quartile of circulating HSPA2 had increased incident heart failure and cardiovascular death vs. all other quartiles.</p><p><strong>Conclusion: </strong>DM is characterized by lower Erbb3 and higher Hspa2 expression in the myocardium, with directionally concordant differences in their plasma protein concentration. These are associated with LV dysfunction, incident heart failure, and cardiovascular mortality.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1898-1906"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11629987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046421","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":"Coming around again.","authors":"Clarissa Savko, Mark A Sussman","doi":"10.1093/cvr/cvae219","DOIUrl":"10.1093/cvr/cvae219","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1830-1831"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380107","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":"CircCHSY1 protects hearts against ischaemia/reperfusion injury by enhancing heme oxygenase 1 expression via miR-24-3p.","authors":"Jiliang Tan, Jie Min, Yun Jiang, Shenyan Liu, Minxia Ke, Zhinong Wang, Huang-Tian Yang","doi":"10.1093/cvr/cvae162","DOIUrl":"10.1093/cvr/cvae162","url":null,"abstract":"<p><strong>Aims: </strong>Circular RNAs (circRNAs) are important players involved in a variety of physiological and pathological processes. However, their functions and mechanisms during myocardial ischaemic injury and protection remain largely unknown. We recently found significant alterations of many circRNAs including circCHSY1 following myocardial ischaemia/reperfusion (I/R) injury, whereas their exact functions are unclear. Here, we investigated the roles of circCHSY1 in the acute myocardial I/R injury and the potential mechanisms involved.</p><p><strong>Methods and results: </strong>The expression of circCHSY1 was detected in cardiomyocytes from mouse, rat, and human embryonic stem cells (hESC-CMs). It was further up-regulated in mouse I/R (30 min/24 h) hearts, oxygen glucose deprivation/reperfusion (OGD/R, 6 h/2 h) primary neonatal rat ventricular cardiomyocytes (NRCMs) and OGD/R (48 h/2 h) hESC-CMs. Adenovirus-mediated circCHSY1 overexpression significantly decreased infarct size and lactate dehydrogenase (LDH) release in mouse I/R hearts. Consistently, circCHSY1 overexpression reduced the LDH release in the OGD/R NRCMs and hESC-CMs, improved cell viability, and preserved mitochondrial function in the OGD/R NRCMs, whereas there were no significant differences in cell viability and LDH release between the OGD/R NRCMs with and without small interfering RNA (siRNA)-mediated circCHSY1 knockdown. Mechanistically, circCHSY1 was detected to bind with miR-24-3p analysed by dual-luciferase assay and RNA pull-down assays. CircCHSY1 overexpression-mediated protective effects on cells and mitochondria in OGD/R NRCMs were reversed by the miR-24-3p mimic. Furthermore, dual-luciferase assay showed that miR-24-3p was directly bound to heme oxygenase 1 (HO1) via its 3'UTR. The protein level of HO1 was down-regulated by miR-24-3p mimic in OGD/R NRCMs but enhanced by the circCHSY1 overexpression in vitro and in vivo. Functionally, the HO1 knockdown by adenovirus in vivo and by siRNA in vitro eliminated cardioprotective effects of circCHSY1 overexpression.</p><p><strong>Conclusion: </strong>CircCHSY1 is up-regulated following myocardial I/R injury. The higher level of circCHSY1 protects I/R hearts and cardiomyocytes. The protection of circCHSY1 is mediated through enhancement of the HO1 level, resulting in preserving mitochondrial homoeostasis via targeting miR-24-3p in cardiomyocytes. These findings suggest circCHSY1 as a protective factor.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1924-1938"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854944","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":"Leveraging metabolism for better outcomes in heart failure.","authors":"Yann Huey Ng, Yen Chin Koay, Francine Z Marques, David M Kaye, John F O'Sullivan","doi":"10.1093/cvr/cvae216","DOIUrl":"10.1093/cvr/cvae216","url":null,"abstract":"<p><p>Whilst metabolic inflexibility and substrate constraint have been observed in heart failure for many years, their exact causal role remains controversial. In parallel, many of our fundamental assumptions about cardiac fuel use are now being challenged like never before. For example, the emergence of sodium-glucose cotransporter 2 inhibitor therapy as one of the four 'pillars' of heart failure therapy is causing a revisit of metabolism as a key mechanism and therapeutic target in heart failure. Improvements in the field of cardiac metabolomics will lead to a far more granular understanding of the mechanisms underpinning normal and abnormal human cardiac fuel use, an appreciation of drug action, and novel therapeutic strategies. Technological advances and expanding biorepositories offer exciting opportunities to elucidate the novel aspects of these metabolic mechanisms. Methodologic advances include comprehensive and accurate substrate quantitation such as metabolomics and stable-isotope fluxomics, improved access to arterio-venous blood samples across the heart to determine fuel consumption and energy conversion, high quality cardiac tissue biopsies, biochemical analytics, and informatics. Pairing these technologies with recent discoveries in epigenetic regulation, mitochondrial dynamics, and organ-microbiome metabolic crosstalk will garner critical mechanistic insights in heart failure. In this state-of-the-art review, we focus on new metabolic insights, with an eye on emerging metabolic strategies for heart failure. Our synthesis of the field will be valuable for a diverse audience with an interest in cardiac metabolism.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1835-1850"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342269","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":"Calciprotein particle counts associate with vascular remodelling in chronic kidney disease.","authors":"Lian Feenstra, Melanie Reijrink, Andreas Pasch, Edward R Smith, Lotte M Visser, Marian Bulthuis, Monique E Lodewijk, Mirjam F Mastik, Marcel J W Greuter, Riemer H J A Slart, Douwe J Mulder, Robert A Pol, Charlotte A Te Velde-Keyzer, Guido Krenning, Jan-Luuk Hillebrands","doi":"10.1093/cvr/cvae164","DOIUrl":"10.1093/cvr/cvae164","url":null,"abstract":"<p><strong>Aims: </strong>Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with the development of vascular calcification (VC) in chronic kidney disease (CKD). Although recent studies have been focusing on associations of CPPs with the presence of VC in CKD, insights in the underlying processes and mechanisms by which CPPs might aggravate VC and vascular dysfunction in vivo are currently lacking. Here, we assessed the overall burden of abdominal VC in healthy kidney donors and CKD patients and subsequently performed transcriptome profiling in the vascular tissue obtained from these subjects, linking outcome to CPP counts and calcification propensity.</p><p><strong>Methods and results: </strong>Calcification scores were quantified in renal arteries, iliac arteries, and abdominal aorta using computed tomography (CT) scans of kidney donors and CKD patients. The vascular tissue was collected from kidney donors (renal artery) and CKD patients (iliac artery), after which bulk RNA sequencing and gene set enrichment analysis (GSEA) were performed on a subset of patients. Calcification propensity (crystallization time, T50) was measured using nephelometry and CPP counts with microparticle flow cytometric analysis. Increased calcification scores (based on CT) were found in CKD patients compared to kidney donors. Transcriptome profiling revealed enrichment for processes related to endothelial activation, inflammation, extracellular matrix (ECM) remodelling, and ossification in CKD vascular biopsies compared to kidney donors. Calcification propensity was increased in CKD, as well as CPP counts, with the latter being significantly associated with markers of vascular remodelling.</p><p><strong>Conclusion: </strong>Our findings reveal that CKD is characterized by systemic VC with increased calcification propensity and CPP counts. Transcriptome profiling showed altered vascular gene expression with enrichment for endothelial activation, inflammation, ECM remodelling, and ossification. Moreover, we demonstrate, for the first time, that vascular remodelling processes are associated with increased circulating CPP counts. Interventions targeting CPPs are promising avenues for alleviating vascular remodelling and VC in CKD.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1953-1966"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11629976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892982","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":"Minimizing gut microbiome confounding factors in cardiovascular research.","authors":"Rikeish R Muralitharan, Jan W Buikema, Francine Z Marques","doi":"10.1093/cvr/cvae228","DOIUrl":"10.1093/cvr/cvae228","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"e60-e62"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567402","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":"Hypoxia-responsive zinc finger E-box-binding homeobox 2 (ZEB2) regulates a network of calcium-handling genes in the injured heart.","authors":"Monika M Gladka, Arwa Kohela, Anne E de Leeuw, Bas Molenaar, Danielle Versteeg, Lieneke Kooijman, Mariska van Geldorp, Willem B van Ham, Rocco Caliandro, Jody J Haigh, Toon A B van Veen, Eva van Rooij","doi":"10.1093/cvr/cvae163","DOIUrl":"10.1093/cvr/cvae163","url":null,"abstract":"<p><strong>Aims: </strong>Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable improvement in managing the progression of heart disease, developing effective therapies for heart failure (HF) remains a challenge. A better understanding of molecular mechanisms that maintain proper Ca2+ levels and contractility in the injured heart could be of therapeutic value.</p><p><strong>Methods and results: </strong>Here, we report that transcription factor zinc finger E-box-binding homeobox 2 (ZEB2) is induced by hypoxia-inducible factor 1-alpha (HIF1α) in hypoxic cardiomyocytes and regulates a network of genes involved in Ca2+ handling and contractility during ischaemic heart disease. Gain- and loss-of-function studies in genetic mouse models revealed that ZEB2 expression in cardiomyocytes is necessary and sufficient to protect the heart against ischaemia-induced diastolic dysfunction and structural remodelling. Moreover, RNA sequencing of ZEB2-overexpressing (Zeb2 cTg) hearts post-injury implicated ZEB2 in regulating numerous Ca2+-handling and contractility-related genes. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban at both serine-16 and threonine-17, implying enhanced activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), thereby augmenting SR Ca2+ uptake and contractility. Furthermore, we observed a decrease in the activity of Ca2+-dependent calcineurin/NFAT signalling in Zeb2 cTg hearts, which is the main driver of pathological cardiac remodelling. On a post-transcriptional level, we showed that ZEB2 expression can be regulated by the cardiomyocyte-specific microRNA-208a (miR-208a). Blocking the function of miR-208a with anti-miR-208a increased ZEB2 expression in the heart and effectively protected from the development of pathological cardiac hypertrophy.</p><p><strong>Conclusion: </strong>Together, we present ZEB2 as a central regulator of contractility and Ca2+-handling components in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in regulating Ca2+ homeostasis in cardiomyocytes is an essential step towards the development of improved therapies for HF.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1869-1883"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280710","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":"Corrigendum to: Transient stabilization of human cardiovascular progenitor cells from human pluripotent stem cells in vitro reflects stage-specific heart development in vivo.","authors":"","doi":"10.1093/cvr/cvae172","DOIUrl":"10.1093/cvr/cvae172","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1985"},"PeriodicalIF":10.2,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016473","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}