Cardiovascular Research最新文献

{"title":"When cell mechanics meets epitranscriptomics: reduction of m6A in Piezo2 RNA ameliorates cardiac fibrosis.","authors":"Gloria Garoffolo, Maurizio Pesce","doi":"10.1093/cvr/cvae247","DOIUrl":"10.1093/cvr/cvae247","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2158-2159"},"PeriodicalIF":10.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799315","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":"GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.","authors":"Minoru Takaoka, John A Tadross, Ali B A K Al-Hadithi, Xiaohui Zhao, Rocío Villena-Gutiérrez, Jasper Tromp, Shazia Absar, Marcus Au, James Harrison, Anthony P Coll, Stefan J Marciniak, Debra Rimmington, Eduardo Oliver, Borja Ibáñez, Adriaan A Voors, Stephen O'Rahilly, Ziad Mallat, Jane C Goodall","doi":"10.1093/cvr/cvae214","DOIUrl":"10.1093/cvr/cvae214","url":null,"abstract":"<p><strong>Aims: </strong>Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A.</p><p><strong>Methods and results: </strong>Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure.</p><p><strong>Conclusion: </strong>Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2249-2260"},"PeriodicalIF":10.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307167","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":"Correction to: Modulation of lncRNA links endothelial glycocalyx to vascular dysfunction of tyrosine kinase inhibitor.","authors":"","doi":"10.1093/cvr/cvae233","DOIUrl":"10.1093/cvr/cvae233","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2321"},"PeriodicalIF":10.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589605","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":"Inflammation and heart failure: are we facing a 'hedgehog's dilemma'?","authors":"Stefano Ministrini, Giovanni G Camici","doi":"10.1093/cvr/cvae246","DOIUrl":"10.1093/cvr/cvae246","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2155-2157"},"PeriodicalIF":10.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643714","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":"Cellular communication network factor 2 regulates smooth muscle cell transdifferentiation and lipid accumulation in atherosclerosis.","authors":"Qian Xu, Jisheng Sun, Claire M Holden, Hildebrando Candido Ferreira Neto, Ti Wang, Chiyuan Zhang, Zuli Fu, Giji Joseph, Ruizheng Shi, Jinhu Wang, Andrew Leask, W Robert Taylor, Zhiyong Lin","doi":"10.1093/cvr/cvae215","DOIUrl":"10.1093/cvr/cvae215","url":null,"abstract":"<p><strong>Aims: </strong>Accruing evidence illustrates an emerging paradigm of dynamic vascular smooth muscle cell (SMC) transdifferentiation during atherosclerosis progression. However, the molecular regulators that govern SMC phenotype diversification remain poorly defined. This study aims to elucidate the functional role and underlying mechanisms of cellular communication network factor 2 (CCN2), a matricellular protein, in regulating SMC plasticity in the context of atherosclerosis.</p><p><strong>Methods and results: </strong>In both human and murine atherosclerosis, an up-regulation of CCN2 is observed in transdifferentiated SMCs. Using an inducible murine SMC CCN2 deletion model, we demonstrate that SMC-specific CCN2 knockout mice are hypersusceptible to atherosclerosis development as evidenced by a profound increase in lipid-rich plaques along the entire aorta. Single-cell RNA sequencing studies reveal that SMC deficiency of CCN2 positively regulates machinery involved in endoplasmic reticulum stress, endocytosis, and lipid accumulation in transdifferentiated macrophage-like SMCs during the progression of atherosclerosis, findings recapitulated in CCN2-deficient human aortic SMCs.</p><p><strong>Conclusion: </strong>Our studies illuminate an unanticipated protective role of SMC-CCN2 against atherosclerosis. Disruption of vascular wall homeostasis resulting from vascular SMC CCN2 deficiency predisposes mice to atherosclerosis development and progression.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2191-2207"},"PeriodicalIF":10.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375136","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":"Acetylation-ubiquitination crosstalk of DJ-1 mediates microcalcification formation in diabetic plaques via collagen-matrix vesicles interaction","authors":"Zhen Sun, Lihua Li, Yao Wu, Lili Zhang, Guangyao Zang, Yongjiang Qian, Haipeng Yao, Xiang Mao, Zhongqun Wang","doi":"10.1093/cvr/cvae263","DOIUrl":"https://doi.org/10.1093/cvr/cvae263","url":null,"abstract":"Aim Microcalcification increases the vulnerability of plaques and has become an important driver of acute cardiovascular events in diabetic patients. However, the regulatory mechanisms remain unclear. DJ-1, a multifunctional protein, may play a potential role in the development of diabetic complications. Therefore, this study aims to explore the relationship between DJ-1 and microcalcification in diabetic plaques and investigate the mechanisms. Methods and results The regulatory relationship between DJ-1 and diabetic vascular microcalcification was determined in anterior tibial arteries from diabetic foot amputated patients, a diabetic apolipoprotein E-deficient (ApoE-/-) mouse model, and a vascular smooth muscle cell (VSMC) model. The ubiquitination and acetylation levels of DJ-1 were detected, and the acetylation-ubiquitination crosstalk was explored. Then, the regulatory effects of DJ-1 on receptor for advanced glycation end products (RAGE) were clarified. Further, the role of DJ-1 in collagen- matrix vesicles (MVs) interaction in diabetic microenvironment was observed. The collagen interacting surface protein of MVs was verified with proteomics and the biomimetic MVs model. In clinical samples, the number of microcalcification nodules in anterior tibial artery plaques was negatively correlated with DJ-1 expression. In diabetic ApoE-/- mice and VSMCs models, knocking down DJ-1 significantly increased the number of microcalcified nodules. N-acetyltransferase 10 (NAT10) was an acetyltransferase of DJ-1. NAT10 could crosstalk the ubiquitination of DJ-1 and enhance the ubiquitination of DJ-1 by E3 ubiquitin ligase tripartite motif-containing protein 32 (TRIM32). Besides, the knockdown of DJ-1 activated signal transducer and activator of transcription 1 (STAT1), and then STAT1 could bind to RAGE promoter, thus upregulating RAGE. Furthermore, the knockdown of DJ-1 significantly promoted collagen-MVs interaction in diabetic microenvironment. Milk fat globule epidermal growth factor 8 (MFGE8) may serve as a collagen-interacting protein. The coating of MFGE8 protein could increase the interaction between collagen and biomimetic MVs. Conclusion In the diabetic microenvironment, DJ-1 was a protective factor for vascular microcalcification. NAT10- and TRIM32-mediated acetylation-ubiquitination crosstalk resulted in the degradation of DJ-1. The decrease of DJ-1 could activate DJ-1/STAT1/RAGE microcalcification signal. Further, under the stimulation of DJ-1-mediated microcalcification signal, VSMCs released MVs with high abundance of MFGE8. MFGE8 promoted collagen-MVs interaction and finally accelerated the formation of microcalcification.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"52 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901710","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":"Iron, lipid peroxidation and ferroptosis play pathogenic roles in atherosclerosis","authors":"Swetha Jinson, Ziyang Zhang, Graeme I Lancaster, Andrew J Murphy, Pooranee K Morgan","doi":"10.1093/cvr/cvae270","DOIUrl":"https://doi.org/10.1093/cvr/cvae270","url":null,"abstract":"Oxidation of lipids, excessive cell death and iron deposition are prominent features of human atherosclerotic plaques. While extensive research has established the detrimental roles of lipid oxidation and apoptosis in atherosclerosis development, the involvement of iron in atherogenesis is not yet fully understood. With the emergence of an iron-dependent form of cell death termed ferroptosis, new attention has been brought to the complex interplay among iron, ferroptosis and atherosclerosis. Mechanistically, ferroptosis is caused by the lethal accumulation of iron-mediated lipid peroxides. Emerging studies have underscored ferroptosis as a contributor to worsened atherosclerosis. Herein, we review the evidence that oxidative damage and iron overload in the context of atherosclerosis may promote ferroptosis within plaques. Furthermore, we summarize recent findings of lipid peroxidation, thereby potentially ferroptosis, in various plaque cell types—such as endothelial cells, macrophages, dendritic cells, T cells, and vascular smooth muscle cells—across different stages of atherosclerosis. Understanding how these processes influence atherosclerotic plaque progression may permit targeting stage-dependent ferroptosis in each cell population and could provide a rationale for developing cell type-specific intervention strategies to mitigate atherogenic ferroptosis effectively.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"36 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902269","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":"Brainstem C1 neurons mediate heart failure decompensation and mortality during acute salt loading","authors":"Karla G Schwarz, Katherin V Pereyra, Esteban Díaz-Jara, Sinay C Vicencio, Rodrigo Del Rio","doi":"10.1093/cvr/cvae261","DOIUrl":"https://doi.org/10.1093/cvr/cvae261","url":null,"abstract":"Aims Heart failure (HF) is an emerging epidemic worldwide. Despite advances in treatment, the morbidity and mortality rate of HF remain high, and the global prevalence continues to rise. Common clinical features of HF include cardiac sympathoexcitation, disordered breathing, and kidney dysfunction; kidney dysfunction strongly contributes to sodium retention and fluid overload, leading to poor outcomes of HF patients. We have previously shown that brainstem pre-sympathetic neurons (C1) from the rostral ventrolateral medulla (RVLM) play a key role in sympathetic regulation in experimental models of HF. However, the role of RVLM-C1 neurons during salt-loading in the context of HF is unknown. This study tests whether RVLM C1 neurons drive cardiorespiratory decompensation, and ultimately lead to sudden death in HF rats. Methods and Results Adult male Sprague-Dawley rats underwent arterio-venous shunt to induce HF with preserved ejection fraction (HFpEF). Two-weeks after HFpEF induction, bilateral selective ablation of RVLM C1 neurons was performed using anti-dopamine β-hydroxylase-saporin toxin (DβH-SAP). Animals were then fed a high Na+ diet (3% Na+ in food and 2% Na+ in water) for 3 weeks to induce compensated-to-decompensated HF state transition. Echocardiography, cardiac autonomic function, breathing function, and survival were assessed during the progression of HF. Salt loading resulted in marked decompensation in HF rats, as evidenced by a significant increase in mortality risk (mortality: 100% vs. 10% HFpEF+Na+ vs. HFpEF). Furthermore, HFpEF+Na+ animals showed a further increase in cardiac sympathetic drive and more severe disordered breathing, including higher hypoxia-related epochs (i.e. apneas/hypopneas), compared to HF. Ablation of RVLM C1 neurons partly reduced the excessive cardiac sympathoexcitation during salt loading in HF, improved the exaggerated disordered breathing in HFpEF+Na+ rats, and reduced decompensation-linked mortality. We found that hypoxia, but not high sodium, was the major contributor to impaired calcium handling in isolated adult cardiomyocytes. Conclusion Our results strongly suggest that RVLM C1 neurons contribute to acute HF decompensation during salt loading by a mechanism encompassing further increases in sympathetic outflow and hypoxia-related breathing disorders. This mechanism may ultimately impact cardiac contractility through cardiomyocyte calcium mishandling, increasing morbidity and mortality.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"114 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901700","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":"Meis transcription factors regulate cardiac conduction system development and adult function.","authors":"Noelia Muñoz-Martín, Ana Simon-Chica, Covadonga Díaz-Díaz, Vanessa Cadenas, Susana Temiño, Isaac Esteban, Andreas Ludwig, Barbara Schormair, Juliane Winkelmann, Veronika Olejnickova, David Sedmera, David Filgueiras-Rama, Miguel Torres","doi":"10.1093/cvr/cvae258","DOIUrl":"https://doi.org/10.1093/cvr/cvae258","url":null,"abstract":"<p><strong>Aims: </strong>The Cardiac Conduction System (CCS) is progressively specified during development by interactions among a discrete number of Transcriptions Factors that ensure its proper patterning and the emergence of its functional properties. Meis genes encode homeodomain transcription factors (TFs) with multiple roles in mammalian development. In humans, Meis genes associate with congenital cardiac malformations and alterations of cardiac electrical activity, however the basis for these alterations has not been established. Here we studied the role of Meis transcription factors in cardiomyocyte development and function during mouse development and adult life.</p><p><strong>Methods and results: </strong>We studied Meis1 and Meis2 conditional deletion mouse models that allowed cardiomyocyte-specific elimination of Meis function during development and inducible elimination of Meis function in cardiomyocytes of the adult CCS. We studied cardiac anatomy, contractility and conduction. We report that Meis factors are global regulators of cardiac conduction, with a predominant role in the CCS. While constitutive Meis deletion in cardiomyocytes led to congenital malformations of the arterial pole and atria, as well as defects in ventricular conduction, Meis elimination in cardiomyocytes of the adult CCS produced sinus node dysfunction and delayed atrio-ventricular conduction. Molecular analyses unraveled Meis-controlled molecular pathways associated with these defects. Finally, we studied in transgenic mice the activity of a Meis1 human enhancer related to an SNP associated by GWAS to PR elongation and found that the transgene drives expression in components of the atrio-ventricular conduction system.</p><p><strong>Conclusions: </strong>Our study identifies Meis TFs as essential regulators of the establishment of cardiac conduction function during development and its maintenance during adult life. In addition, we generated animal models and identified molecular alterations that will ease the study of Meis-associated conduction defects and congenital malformations in humans.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846171","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":"SerpinB1 targeting safeguards against pathological cardiac hypertrophy and remodelling by suppressing cardiomyocyte pyroptosis and inflammation initiation.","authors":"Cong Lan, Gangyao Fang, Xiuchuan Li, Xiao Chen, Yingmei Chen, Tao Hu, Xuenan Wang, Huiling Cai, Jiajin Hao, Haoran Li, Yan Zhang, Ke Peng, Zaicheng Xu, Dachun Yang, Xia Kang, Qian Xin, Yongjian Yang","doi":"10.1093/cvr/cvae241","DOIUrl":"https://doi.org/10.1093/cvr/cvae241","url":null,"abstract":"<p><strong>Aims: </strong>While the pivotal role of inflammation in pathological cardiac hypertrophy and remodelling is widely acknowledged, the mechanisms triggering inflammation initiation remain largely obscure. This study aims to elucidate the role and mechanism of serpin family B member 1 (SerpinB1) in pro-inflammatory cardiomyocyte pyroptosis, heart inflammation, and cardiac remodelling.</p><p><strong>Methods and results: </strong>C57BL/6J wild-type, inducible cardiac-specific SerpinB1 overexpression or knockout mice underwent transverse aortic constriction (TAC) surgery. Cardiac hypertrophy and remodelling were assessed through echocardiography and histology. Cardiomyocyte pyroptosis and heart inflammation were monitored. Adeno-associated virus 9 -mediated gene manipulations and molecular assays were employed to explore the mechanisms through which SerpinB1 regulates cardiomyocyte pyroptosis and heart inflammation. Finally, recombinant mouse SerpinB1 protein (rSerpinB1) was administrated both in vivo through osmotic minipump delivery and in vitro to investigate the therapeutic potential of SerpinB1 in cardiac remodelling. Myocardial SerpinB1 overexpression was up-regulated shortly upon TAC or phenylephrine challenge, with no further elevation during prolonged hypertrophic stimuli. It is important to note that cardiac-specific overexpression of SerpinB1 markedly attenuated TAC-induced cardiac remodelling, while deletion of SerpinB1 exacerbated it. At the mechanistic level, SerpinB1 gain-of-function inhibited cardiomyocyte pyroptosis and inflammation in hypertrophic hearts; the protective effect was nullified by overexpression of either cleaved N-terminal gasdermin D or cleaved caspase-1. Co-immunoprecipitation and confocal assays confirmed that SerpinB1 directly interacts with caspase-1 in cardiomyocytes. Remarkably, rSerpinB1 replicated the cardioprotective effect against cardiac hypertrophy and remodelling.</p><p><strong>Conclusion: </strong>SerpinB1 safeguards against pathological cardiac hypertrophy and remodelling by impeding cardiomyocyte pyroptosis to suppress inflammation initiation, achieved through interaction with caspase-1 to inhibit its activation. Targeting SerpinB1 could represent a novel therapeutic strategy for treating pathological cardiac hypertrophy and remodelling.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833364","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}