Cardiovascular Research最新文献

{"title":"TAOK1 suppression improves doxorubicin-induced cardiomyopathy by preventing cardiomyocyte death and dysfunction","authors":"Takaomi Suga, Tomoya Kitani, Masaya Kogure, Masatsugu Oishi, Fumiaki Ito, Atsushi Hoshino, Takehiro Ogata, Koji Ikeda, Satoaki Matoba","doi":"10.1093/cvr/cvaf022","DOIUrl":"https://doi.org/10.1093/cvr/cvaf022","url":null,"abstract":"Aims Doxorubicin (DOX) is one of the most effective chemotherapeutic agents for various types of cancers. However, DOX often causes cardiotoxicity, which is referred to as DOX-induced cardiomyopathy (DIC). Despite extensive research, only a limited number of effective treatments are currently available. In this study, we aimed to identify a potential therapeutic target for DIC by preventing DOX-induced cell injury in cardiomyocytes. Methods and results We performed a kinome-wide CRISPR gene knockout screen in human cardiomyocytes derived from pluripotent stem cells (hPSC-CMs) and identified a member of the STE20 kinase family, thousand and one amino acid protein kinase 1 (TAOK1) as a potential regulator of DOX-induced cardiomyocyte death. Using CRISPR-mediated gene knockout and siRNA-mediated gene knockdown, we demonstrated that TAOK1 suppression improved DOX-induced cardiomyocyte death and dysfunction, including sarcomere disarray, contractile dysfunction, DNA damage, and mitochondrial dysfunction in hPSC-CMs. Transcriptome analysis using RNA-Seq also showed that DOX-induced mitochondrial dysfunction was attenuated by TAOK1 suppression. In contrast to the protective role of TAOK1 against DOX toxicity in cardiomyocytes, TAOK1 suppression did not induce DOX resistance in human cancer cell lines. DOX-induced activation of p38 MAPK was markedly attenuated in TAOK1-knockout hPSC-CMs. Furthermore, DOX-induced cardiomyocyte death and disruption of mitochondrial membrane potential were augmented by TAOK1 overexpression, which was partially attenuated by an inhibitor or knockdown of p38 MAPK or an apoptosis inhibitor. Finally, we demonstrated that TAOK1 suppression using AAV-mediated gene silencing attenuated DOX-induced myocardial damage, including myocardial fibrosis, apoptosis, and cardiomyocyte atrophy, resulting in improved cardiac function in a mouse model of DIC. Conclusion Our results indicate that TAOK1 suppression is a promising therapeutic approach for treating DIC in patients with cancer and highlight the advantages of hPSC-CMs as a platform to study drug-induced cardiotoxicity.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"29 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443241","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":"https://doi.org/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 datasets 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 remodeling, 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 remodeling.</p><p><strong>Conclusions: </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":""},"PeriodicalIF":10.2,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiotensin 1-7 and a TERT activator individually restore vasodilatory capacity within the microcirculation previous SARS-CoV-2 infection.","authors":"Yoshinori Nishijima, Shelby N Hader, Erin C Birch, Yiliang Chen, Michael E Widlansky, Andreas M Beyer","doi":"10.1093/cvr/cvaf020","DOIUrl":"https://doi.org/10.1093/cvr/cvaf020","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405702","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":"Stretch regulation of β2-Adrenoceptor signalling in cardiomyocytes requires caveolae.","authors":"Jiarong Fu, Catherine Mansfield, Ivan Diakonov, Aleksandra Judina, Matthew Delahaye, Navneet Bhogal, Jose L Sanchez-Alonso, Timothy Kamp, Julia Gorelik","doi":"10.1093/cvr/cvae265","DOIUrl":"https://doi.org/10.1093/cvr/cvae265","url":null,"abstract":"<p><strong>Aims: </strong>Caveolin-3 is essential for the formation of caveolae in cardiomyocytes. Caveolar microdomains have been shown to regulate the distribution of signalling proteins such as beta-adrenoceptors (βAR) and may act as membrane reserves to protect the cell from damage during the mechanical stretch. Myocardial stretch occurs during haemodynamic overload and may be normal (e.g. exercise) or pathological (e.g. heart failure); therefore, it is important to understand the effect of stretch on signalling pathways associated with mechanosensitive structures, such as caveolae. In this study, we investigate the role of caveolae in regulating the effect of stretch on βAR-signalling.</p><p><strong>Methods and results: </strong>We used osmotic swelling of isolated rat ventricular cardiomyocytes as a method to stretch the cell membrane and investigate the effect of βAR stimulation on cyclic adenosine monophosphate (cAMP) activity and contractility. βAR response was measured using a Förster Resonance Energy Transfer reporter for the second messenger cAMP and using CytoCypher for the measurement of cell contractility. β1AR and β2AR blockers were used to selectively allow stimulation of β2AR and β1AR, respectively. We also investigated the effect of stretch on βAR response to isoprenaline stimulation in left ventricular trabeculae dissected from control and cardiac-specific caveolin-3 knock-out mice (Cav3KO). Stretching trabeculae produces increased baseline adenylyl cyclase activity and a higher level of cAMP and a greater β2AR-induced positive inotropy after stimulation of the β2AR but not β1AR, by isoprenaline. Similar findings were confirmed for isolated myocytes subjected to hypoosmotic conditions. In isolated cardiomyocytes, caveolae depletion using methyl-beta-cyclodextrin or Cav3KO abolished the increase in β2AR response induced by stretch.</p><p><strong>Conclusion: </strong>Our study reveals a stretch-regulation of the β2AR signalling pathway, which requires functional caveolae. This indicates caveolae are mechanosensitive membrane domains that undergo structural and functional changes in response to stretch, thus leading to mechanical regulation of caveolae-associated signalling pathways.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405715","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":"Colchicine and stabilization of coronary artery plaques.","authors":"Valtteri Muroke, Jean-Claude Tardif","doi":"10.1093/cvr/cvaf019","DOIUrl":"https://doi.org/10.1093/cvr/cvaf019","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405705","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":"Immune cells and arrhythmias","authors":"Joshua A Keefe, Jian Wang, Jiangping Song, Li Ni, Xander Wehrens","doi":"10.1093/cvr/cvaf017","DOIUrl":"https://doi.org/10.1093/cvr/cvaf017","url":null,"abstract":"Cardiac arrhythmias are a significant cause of morbidity and mortality worldwide. Emerging evidence has demonstrated that resident and infiltrating cardiac immune cells play direct, mechanistic roles in arrhythmia onset and progression. In this review, we provide a comprehensive summary and expert commentary on the role of each immune cell subtype in the pathogenesis of atrial and ventricular arrhythmias.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"78 5 Pt 1 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401241","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":"Emerging role of Cellular communication network factor 2 (CCN2) as a guardian of smooth muscle cell phenotype and vascular integrity.","authors":"J H Larsen, L B Steffensen","doi":"10.1093/cvr/cvaf015","DOIUrl":"https://doi.org/10.1093/cvr/cvaf015","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390376","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":"https://doi.org/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":""},"PeriodicalIF":10.2,"publicationDate":"2025-02-10","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}

{"title":"Redirecting glucose into anabolic pathways participates in the protective effects of NRF2 activation in the heart under stress.","authors":"Thomas Eschenhagen","doi":"10.1093/cvr/cvaf003","DOIUrl":"https://doi.org/10.1093/cvr/cvaf003","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381698","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":"Interleukin-37 attenuates aortic valve lesions by inhibiting m6A-mediated IRAK-M degradation","authors":"Gaopeng Xian, Rong Huang, Dongtu Hu, Minhui Xu, Yangchao Chen, Hao Ren, Dingli Xu, Qingchun Zeng","doi":"10.1093/cvr/cvaf012","DOIUrl":"https://doi.org/10.1093/cvr/cvaf012","url":null,"abstract":"Aims Calcific aortic valve disease (CAVD) has become an increasingly important global medical problem without effective pharmacological intervention. Accumulating evidence indicates that aortic valve calcification is driven by inflammation. Interleukin-1 receptor-associated kinase M (IRAK-M) is a well-known negative regulator of inflammation, but its role in CAVD remains unclear. Methods and Results Here, we stimulated aortic valve interstitial cells (AVICs) with low-dose lipopolysaccharide (LPS) to mimic the inflammatory response in aortic valve calcification and observed the expression pattern of IRAK-M. Furthermore, we generated IRAK-M-/- mice to explore the effect of IRAK-M deficiency on the aortic valve in vivo. Additionally, overexpression and knockdown experiments were performed to verify the role of IRAK-M in AVICs. MeRIP‒qPCR was used to detect the N6-methyladenosine (m6A) level of IRAK-M, and recombinant interleukin (IL)-37-treated AVICs were used to determine the regulatory relationship between IL-37 and IRAK-M. We found that IRAK-M expression was upregulated in the early stages of inflammation as part of a negative feedback mechanism to modulate the immune response. However, persistent inflammation increased overall m6A levels, ultimately leading to reduced IRAK-M expression. In vivo, IRAK-M-/- mice exhibited a propensity for aortic valve thickening and calcification. Overexpression and knockdown experiments showed that IRAK-M inhibited inflammation and osteogenic responses in AVICs. In addition, IL-37 restored IRAK-M expression by inhibiting m6A-mediated IRAK-M degradation to suppress inflammation and aortic valve calcification. Conclusions Our findings confirm that inflammation and epigenetic modifications synergistically regulate IRAK-M expression. Moreover, IRAK-M represents a potential target for mitigating aortic valve calcification. Meanwhile, IL-37 exhibited inhibitory effects on CAVD development both in vivo and in vitro, giving us hope that CAVD can be treated with drugs rather than surgery.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"14 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258592","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}