Cardiovascular Research最新文献

{"title":"Single cell RNA sequencing of hematopoietic cells in fresh and frozen human atheroma tissue.","authors":"Herra Ahmad, J K Gopakumar, Daniel C Nachun, Lisa Ma, Jessica D'Addabbo, Xianxi Huang, Tiffany Koyano, Jack Boyd, Y Joseph Woo, Robyn Fong, Oliver Aalami, Patricia K Nguyen, Siddhartha Jaiswal","doi":"10.1093/cvr/cvaf014","DOIUrl":"https://doi.org/10.1093/cvr/cvaf014","url":null,"abstract":"<p><strong>Aims: </strong>Single-cell RNA sequencing (scRNA-seq) is a powerful method for exploring the cellular heterogeneity within human atheroma but typically requires fresh tissue to preserve cell membrane integrity, limiting the feasibility of large-scale biobanking for later analysis. The aim of this study was to determine whether cryopreservation of fragile and necrotic atheroma tissue affects the viability and transcriptomic profiles of hematopoietic cells in subsequent scRNA-seq analysis, enabling the use of cryopreserved atheroma samples for future research.</p><p><strong>Methods and results: </strong>We performed scRNA-seq on five paired fresh and cryopreserved atheroma samples - three from coronary arteries and two from carotid arteries. Each sample was enzymatically digested, sorted for CD45+ hematopoietic cells, and processed using the 10X Genomics scRNA-seq workflow. Half of each sample was processed immediately, while the other half was cryopreserved in liquid nitrogen for an average of five weeks before thawing and processing. In carotid artery samples, we noted the absence of LYVE1+ macrophages, likely due to the loss of the adventitial layer during endarterectomy procedures. Our results indicated that cryopreservation modestly affected cellular integrity, leading to an increase in the relative abundance of mitochondrial RNA in frozen samples. Minimal differences were observed between fresh and cryopreserved samples in uniquely detected transcripts, cell clustering, or transcriptional profiles within hematopoietic populations.</p><p><strong>Conclusion(s): </strong>Our study demonstrates that cryopreserved human atheroma samples can be successfully profiled using scRNA-seq, with comparable transcriptomic data to that obtained from fresh samples. These findings suggest that cryopreservation is a viable method for biobanking atheroma tissues, facilitating large-scale studies without the need for immediate sample processing.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188419","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":"Cardioprotective effects of a 'twincretin' drug tirzepatide in heart failure following myocardial infarction.","authors":"Rui Shang, Brian Rodrigues","doi":"10.1093/cvr/cvaf006","DOIUrl":"https://doi.org/10.1093/cvr/cvaf006","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188417","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":"CircRNAs increase during vascular cell differentiation and are biomarkers for vascular disease","authors":"Bernd H Northoff, Andreas Herbst, Catharina Wenk, Lena Weindl, Gabor Gäbel, Andre Brezski, Kathi Zarnack, Alina Küpper, Stefanie Dimmeler, Alessandra Moretti, Karl-Ludwig Laugwitz, Stefan Engelhardt, Lars Maegdefessel, Reinier Boon, Stefanie Doppler, Martina Dreßen, Harald Lahm, Rüdiger Lange, Markus Krane, Knut Krohn, Alexander Kohlmaier, Lesca M Holdt, Daniel Teupser","doi":"10.1093/cvr/cvaf013","DOIUrl":"https://doi.org/10.1093/cvr/cvaf013","url":null,"abstract":"Aims The role of circular RNAs (circRNAs) and their regulation in health and disease are poorly understood. Here, we systematically investigated the temporally resolved transcriptomic expression of circRNAs during differentiation of human induced pluripotent stem cells (iPSC) into vascular endothelial cells (EC) and smooth muscle cells (SMC) and explored their potential as biomarkers for human vascular disease. Methods and Results Using high-throughput RNA sequencing and a de novo circRNA detection pipeline, we quantified the daily levels of 31,369 circRNAs in a two-week differentiation trajectory from human stem cells to proliferating mesoderm progenitors to quiescent, differentiated EC and SMC. We detected a significant global increase in RNA circularization, with 397 and 214 circRNAs upregulated &amp;gt; 2 fold (adjusted P &amp;lt; 0.05) in mature EC and SMC, compared with undifferentiated progenitor cells. This global increase in circRNAs was associated with upregulation of host genes and their promoters and a parallel downregulation of splicing factors. Underlying this switch, the proliferation-regulating transcription factor MYC decreased as vascular cells matured, and inhibition of MYC led to downregulation of splicing factors such as SRSF1 and SRSF2 and changes in vascular circRNA levels. Examining the identified circRNAs in arterial tissue samples and in peripheral blood mononuclear cells (PBMC) from patients, we found that circRNA levels decreased in atherosclerotic disease, in contrast to their increase during iPSC maturation into EC and SMC. Using machine learning, we determined that a set of circRNAs derived from COL4A1, COL4A2, HSPG2, and YPEL2 discriminated atherosclerotic from healthy tissue with an AUC of 0.79. CircRNAs from HSPG2 and YPEL2 in blood PBMC samples detected atherosclerosis with an AUC of 0.73. Conclusions Time-resolved transcriptional profiling of linear and circular RNA species revealed that circRNAs provide granular molecular information for disease profiling. The identified circRNAs may serve as blood biomarkers for atherosclerotic vascular disease.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"1 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083758","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":"Incretin-based weight loss therapies and heart failure with preserved ejection fraction: guideline impactful results, but mechanisms unclear.","authors":"Katarzyna Stefanska, Naveed Sattar","doi":"10.1093/cvr/cvaf001","DOIUrl":"https://doi.org/10.1093/cvr/cvaf001","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063880","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":"Downregulation of HDAC2 attenuates ventricular arrhythmias in a mouse model of cardiac hypertrophy through upregulation of KCHIP2 expression.","authors":"Wenjuan Liu, Jianping Liu, Gang Wang, Wanwen Cheng, Haochen Gong, Yujuan Song, Ming Song, Yixin Zhuge, Ying Li, Jie Liu","doi":"10.1093/cvr/cvaf008","DOIUrl":"https://doi.org/10.1093/cvr/cvaf008","url":null,"abstract":"<p><strong>Aims: </strong>Decrease in repolarizing K+ currents, particularly the fast component of transient outward K+ current (Ito,f), prolongs action potential duration (APD) and predisposes the heart to ventricular arrhythmia during cardiac hypertrophy. Histone deacetylases (HDACs) have been suggested to participate in the development of cardiac hypertrophy, and class I HDAC inhibition has been found to attenuate pathological remodeling. This study investigated the potential therapeutic effects of HDAC2 on ventricular arrhythmia in pressure overload-induced cardiac hypertrophy.</p><p><strong>Methods and results: </strong>An in vivo cardiac hypertrophic model was produced by performing transverse aortic constriction (TAC) surgery, and an in vitro cardiomyocyte hypertrophy model by stimulating neonatal rat ventricular myocytes (NRVMs) with phenylephrine (PE). HDAC2 expression was upregulated in TAC mouse hearts and in PE-stimulated cardiomyocytes. Susceptibility to ventricular arrhythmia was increased in TAC mice, while Ito,f was decreased and APD was prolonged in TAC cardiomyocytes. Heart-specific knockdown of HDAC2 (HKD) by RNA interference increased Ito,f, shortened APD and decreased susceptibility to ventricular arrhythmia. Concomitantly, HKD increased the expression of the obligatory β subunit of Ito,f, KChIP2, which is downregulated in hypertrophic hearts. The effects of HKD on KChIP2 expression, Ito,f and APD were also observed in PE-stimulated cardiomyocytes. Mechanistically, HKD increased H3K4me3 abundance and H3K4me3 enrichment at the Kcnip2 promoter in cardiomyocytes. HKD also decreased the expression of KDM5, the H3K4me3 demethylase, which resulted in H3K4me3 upregulation. While investigating the regulatory mechanisms underlying the effect of HDAC2 on KDM5 stability, we identified CNOT4 as the active KDM5 ubiquitinase in cardiomyocytes. HKD increased CNOT4 expression and CNOT4-KDM5 interactions, and thus enhanced the polyubiquitinated degradation of KDM5.</p><p><strong>Conclusions: </strong>HDAC2 inhibition serves as a novel therapeutic strategy for preventing cardiac hypertrophy-associated electrophysiological remodeling. Furthermore, we identified a novel signaling pathway of CNOT4-mediated KDM5 degradation contributing to the upregulation of H3K4me3-mediated KChIP2 expression in response to HDAC2 inhibition.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051749","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":"Cardioprotection with nebivolol in patients undergoing anthracyclines: a randomized placebo-controlled trial.","authors":"Giulio Stefanini, Carmelo Carlo-Stella, Francesco Cannata, Mauro Chiarito, Stefano Figliozzi, Laura Novelli, Costanza Lisi, Sara Bombace, Federica Catapano, Eleonora Indolfi, Cristina Panico, Francesco Corrado, Giovanna Masci, Rita Mazza, Francesca Ricci, Lorenzo Monti, Giuseppe Ferrante, Bernhard Reimers, Armando Santoro, Marco Francone, Bruno R da Costa, Peter Jüni, Gianluigi Condorelli","doi":"10.1093/cvr/cvae266","DOIUrl":"https://doi.org/10.1093/cvr/cvae266","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022164","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":"Modulation of amygdala and hippocampus during anxiety by heart and middle frontal gyrus.","authors":"Gert Pfurtscheller, Beate Rassler, Alberto Porta, Gerhard Schwarz, Maciej Kaminski, Klaus Pfurtscheller, Wolfgang Klimesch","doi":"10.1093/cvr/cvaf007","DOIUrl":"https://doi.org/10.1093/cvr/cvaf007","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000643","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":"Dedicator of Cytokinesis 2 regulates cytoskeletal actin dynamics and is essential for platelet biogenesis and functions","authors":"Jiani Ji, Xulin Xu, Lili Zhang, Shuang Liu, Jiayi Chen, Huihui Gao, Limin Xiang, Yaofeng Li, Hui Xu, Yaobing Chen, Huiqin Xiang, Shuai Chen, Yunyun Han, Zhaoming Tang, Xuanbin Wang, Xiaofeng Shi, Jianhua Mao, Xiaodong Xi, Jinyu Wang, Chao Fang","doi":"10.1093/cvr/cvaf009","DOIUrl":"https://doi.org/10.1093/cvr/cvaf009","url":null,"abstract":"Aims Dedicator of Cytokinesis 2 (DOCK2), a member of the DOCK family of Guanine nucleotide exchange factors that specifically act on the Rho GTPases including Rac and Cdc42, plays pivotal roles in the regulation of leukocyte homeostasis. However, its functions in platelets remain unknown. Methods and Results Using mice with genetic deficiency of DOCK2 (Dock2-/-), we showed that Dock2-/-mice exhibited a macrothrombocytopenic phenotype characterized as decreased platelet count and enlarged platelet size by transmission electron microscopy. Dock2-/- megakaryocytes had reduced polyploidization determined by propidium iodide staining and defective proplatelet formation by confocal microscopy. DOCK2 deficiency led to enriched F-actin level in resting platelets but defective F-actin assembly in activated platelets by phalloidin staining, and mechanistically, attenuated activity of Rac1, unchanged Cdc42 but enhanced RhoA measured by immunoprecipitation of GTP-bound proteins. Immunoblotting analysis showed that Dock2-/- platelets had reduced Immunoreceptor Tyrosine-based Activation Motif signaling downstream of impaired clustering of GPVI receptors determined by stochastic optical reconstruction microscopy. Further, DOCK2 deficiency resulted in reduced density and branches of fibrin fibers in the clots in vitro and diminished platelet aggregation in a microfluidic chamber ex vivo. Dock2-/- platelets exhibited impaired incorporation into a growing thrombus in cremaster arterioles following allogeneic transfusion into a WT recipient, and defective heterotypic interactions with neutrophils in cremaster venules as reflected by decreased platelet-neutrophil aggregate formation in vitro under stirring condition. In addition, myeloid deficiency of DOCK2 caused prolonged tail bleeding times. Finally, pharmacological inhibition of DOCK2 using a small-molecular inhibitor CPYPP suppressed actin dynamics leading to impaired responses to GPVI activation, and defects in platelet spreading, clot retraction, and thrombus formation. Conclusions DOCK2 plays critical roles in the regulation of platelet biogenesis and functions by controlling Rac1 activity and cytoskeletal actin dynamics, and may be a novel target for the treatment of thrombotic and thrombo-inflammatory diseases.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"32 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992060","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":"Therapeutic potential of ketone bodies on exercise intolerance in heart failure: looking beyond the heart","authors":"Shubham Soni, Rachel J Skow, Stephen Foulkes, Mark J Haykowsky, Jason R B Dyck","doi":"10.1093/cvr/cvaf004","DOIUrl":"https://doi.org/10.1093/cvr/cvaf004","url":null,"abstract":"Recent evidence suggests that ketone bodies have therapeutic potential in many cardiovascular diseases including heart failure (HF). Accordingly, this has led to multiple clinical trials that use ketone esters to treat HF patients, which we term ketone therapy. Ketone esters, specifically ketone monoesters, are synthetic compounds which, when consumed, are de-esterified into two β-hydroxybutyrate (βOHB) molecules and increase the circulating βOHB concentration. While many studies have primarily focused on the cardiac benefits of ketone therapy in HF, ketones can have numerous favorable effects in other organs such as the vasculature and skeletal muscle. Importantly, vascular and skeletal muscle dysfunction are also heavily implicated in the reduced exercise tolerance, the hallmark feature in HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction, suggesting that some of the benefits observed in HF in response to ketone therapy may involve these non-cardiac pathways. Thus, we review the evidence suggesting how ketone therapy may be beneficial in improving cardiovascular and skeletal muscle function in HF and identify various potential mechanisms that may be important in the beneficial non-cardiac effects of ketones in HF.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"98 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988651","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":"Intestinal interstitial fluid isolation provides novel insight into the human host-microbiome interface","authors":"Ellen G Avery, Lea-Maxie Haag, Victoria McParland, Sarah M Kedziora, Gabriel J Zigra, Daniela S Valdes, Marieluise Kirchner, Oliver Popp, Sabrina Geisberger, Olivia Nonn, Tine V Karlsen, Gabriele N’Diaye, Alex Yarritu, Hendrik Bartolomaeus, Theda U P Bartolomaeus, Nurana A Tagiyeva, Moritz I Wimmer, Nadine Haase, Yiming D Zhang, Andreas Wilhelm, Gerald Grütz, Olav Tenstad, Nicola Wilck, Sofia K Forslund, Robert Klopfleisch, Anja A Kühl, Raja Atreya, Stefan Kempa, Philipp Mertins, Britta Siegmund, Helge Wiig, Dominik N Müller","doi":"10.1093/cvr/cvae267","DOIUrl":"https://doi.org/10.1093/cvr/cvae267","url":null,"abstract":"Aims The gastrointestinal (GI) tract is composed of distinct sub-regions, which exhibit segment-specific differences in microbial colonization and (patho)physiological characteristics. Gut microbes can be collectively considered as an active endocrine organ. Microbes produce metabolites, which can be taken up by the host and can actively communicate with the immune cells in the gut lamina propria with consequences for cardiovascular health. Variation in bacterial load and composition along the GI tract may influence the mucosal microenvironment and thus be reflected its interstitial fluid (IF). Characterization of the segment-specific microenvironment is challenging and largely unexplored because of lack of available tools. Methods and results Here, we developed methods, namely tissue centrifugation and elution, to collect IF from the mucosa of different intestinal segments. These methods were first validated in rats and mice, and the tissue elution method was subsequently translated for use in humans. These new methods allowed us to quantify microbiota-derived metabolites, mucosa-derived cytokines, and proteins at their site-of-action. Quantification of short-chain fatty acids showed enrichment in the colonic IF. Metabolite and cytokine analyses revealed differential abundances within segments, often significantly increased compared to plasma, and proteomics revealed that proteins annotated to the extracellular phase were site-specifically identifiable in IF. Lipopolysaccharide injections in rats showed significantly higher ileal IL-1β levels in IF compared to the systemic circulation, suggesting the potential of local as well as systemic effect. Conclusion Collection of IF from defined segments and the direct measurement of mediators at the site-of-action in rodents and humans bypasses the limitations of indirect analysis of faecal samples or serum, providing direct insight into this understudied compartment.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"28 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968229","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}