Pub Date : 2024-07-08DOI: 10.1038/s44161-024-00496-y
Hanqiang Deng, Jiasheng Zhang, Yewei Wang, Divyesh Joshi, Xinchun Pi, Sarah De Val, Martin A. Schwartz
Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease. Deng et al. show that endothelial cells respond to high fluid shear stress by KLF2-mediated induction of the BMP–Smad1/5 pathway inhibitor BMPER, resulting in outward vessel remodeling, and apply this knowledge to develop an approach that improves vessel remodeling in mouse models of diabetes.
{"title":"A KLF2-BMPER-Smad1/5 checkpoint regulates high fluid shear stress-mediated artery remodeling","authors":"Hanqiang Deng, Jiasheng Zhang, Yewei Wang, Divyesh Joshi, Xinchun Pi, Sarah De Val, Martin A. Schwartz","doi":"10.1038/s44161-024-00496-y","DOIUrl":"10.1038/s44161-024-00496-y","url":null,"abstract":"Vascular remodeling to match arterial diameter to tissue requirements commonly fails in ischemic disease. Endothelial cells sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Thus, high FSS induces vessel outward remodeling, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS. Smad1/5 limits Akt activation, suggesting that inhibiting Smad1/5 may facilitate outward remodeling. Here we report that high FSS suppresses Smad1/5 by elevating KLF2, which induces the bone morphogenetic protein (BMP) pathway inhibitor, BMP-binding endothelial regulator (BMPER), thereby de-inhibiting Akt. In mice, surgically induced high FSS elevated BMPER expression, inactivated Smad1/5 and induced vessel outward remodeling. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling. Blocking endothelial cell Smad1/5 activation with BMP9/10 blocking antibodies improved vascular remodeling in mouse models of type 1 and type 2 diabetes. Suppression of Smad1/5 is thus a potential therapeutic approach for ischemic disease. Deng et al. show that endothelial cells respond to high fluid shear stress by KLF2-mediated induction of the BMP–Smad1/5 pathway inhibitor BMPER, resulting in outward vessel remodeling, and apply this knowledge to develop an approach that improves vessel remodeling in mouse models of diabetes.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"785-798"},"PeriodicalIF":9.4,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05DOI: 10.1038/s44161-024-00485-1
Liane Jurida, Sebastian Werner, Fabienne Knapp, Bernd Niemann, Ling Li, Dimitri Grün, Stefanie Wirth, Axel Weber, Knut Beuerlein, Christoph Liebetrau, Christoph B. Wiedenroth, Stefan Guth, Baktybek Kojonazarov, Leili Jafari, Norbert Weissmann, Stefan Günther, Thomas Braun, Marek Bartkuhn, Ralph T. Schermuly, Peter Dorfmüller, Xiaoke Yin, Manuel Mayr, M. Lienhard Schmitz, Laureen Czech, Klaus-Dieter Schlüter, Rainer Schulz, Susanne Rohrbach, Michael Kracht
The molecular mechanisms of progressive right heart failure are incompletely understood. In this study, we systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery banding (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signature, protein and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome datasets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans. Using bulk heart transcriptomics of rat models of right and left ventricle failure, Jurida et al. examined transcriptional changes in cardiomyocytes during the progression of heart failure and the overlap with transcriptomics from humans with chronic thromboembolic pulmonary hypertension (CTEPH), identifying more than 50 genes whose expression levels correlate with the severity of right heart disease.
{"title":"A common gene signature of the right ventricle in failing rat and human hearts","authors":"Liane Jurida, Sebastian Werner, Fabienne Knapp, Bernd Niemann, Ling Li, Dimitri Grün, Stefanie Wirth, Axel Weber, Knut Beuerlein, Christoph Liebetrau, Christoph B. Wiedenroth, Stefan Guth, Baktybek Kojonazarov, Leili Jafari, Norbert Weissmann, Stefan Günther, Thomas Braun, Marek Bartkuhn, Ralph T. Schermuly, Peter Dorfmüller, Xiaoke Yin, Manuel Mayr, M. Lienhard Schmitz, Laureen Czech, Klaus-Dieter Schlüter, Rainer Schulz, Susanne Rohrbach, Michael Kracht","doi":"10.1038/s44161-024-00485-1","DOIUrl":"10.1038/s44161-024-00485-1","url":null,"abstract":"The molecular mechanisms of progressive right heart failure are incompletely understood. In this study, we systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery banding (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signature, protein and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome datasets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans. Using bulk heart transcriptomics of rat models of right and left ventricle failure, Jurida et al. examined transcriptional changes in cardiomyocytes during the progression of heart failure and the overlap with transcriptomics from humans with chronic thromboembolic pulmonary hypertension (CTEPH), identifying more than 50 genes whose expression levels correlate with the severity of right heart disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"819-840"},"PeriodicalIF":9.4,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00485-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05DOI: 10.1038/s44161-024-00502-3
Michael P. Lazaropoulos, Andrew A. Gibb, Douglas J. Chapski, Abheya A. Nair, Allison N. Reiter, Rajika Roy, Deborah M. Eaton, Kenneth C. Bedi Jr, Kenneth B. Margulies, Kathryn E. Wellen, Conchi Estarás, Thomas M. Vondriska, John W. Elrod
Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFβ stimulation enhances ACLY nuclear localization and ACLY–SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis. Elrod and colleagues reveal the role of ATP-citrate lyase in myofibroblast differentiation and cardiac fibrosis.
{"title":"Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program","authors":"Michael P. Lazaropoulos, Andrew A. Gibb, Douglas J. Chapski, Abheya A. Nair, Allison N. Reiter, Rajika Roy, Deborah M. Eaton, Kenneth C. Bedi Jr, Kenneth B. Margulies, Kathryn E. Wellen, Conchi Estarás, Thomas M. Vondriska, John W. Elrod","doi":"10.1038/s44161-024-00502-3","DOIUrl":"10.1038/s44161-024-00502-3","url":null,"abstract":"Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFβ stimulation enhances ACLY nuclear localization and ACLY–SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFβ-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis. Elrod and colleagues reveal the role of ATP-citrate lyase in myofibroblast differentiation and cardiac fibrosis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"869-882"},"PeriodicalIF":9.4,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00502-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05DOI: 10.1038/s44161-024-00500-5
Nikolaos G. Frangogiannis
Myofibroblast activation requires nuclear translocation of ATP citrate lyase (ACLY) that triggers chromatin remodeling and the induction of fibrosis-associated genes. ACLY inhibition prevents myofibroblast conversion and causes de-differentiation of myofibroblasts to fibroblasts, indicating a potential therapeutic approach for heart failure.
{"title":"Targeting metabolically activated fibroblasts in the failing heart","authors":"Nikolaos G. Frangogiannis","doi":"10.1038/s44161-024-00500-5","DOIUrl":"10.1038/s44161-024-00500-5","url":null,"abstract":"Myofibroblast activation requires nuclear translocation of ATP citrate lyase (ACLY) that triggers chromatin remodeling and the induction of fibrosis-associated genes. ACLY inhibition prevents myofibroblast conversion and causes de-differentiation of myofibroblasts to fibroblasts, indicating a potential therapeutic approach for heart failure.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"782-784"},"PeriodicalIF":9.4,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-02DOI: 10.1038/s44161-024-00514-z
Andrea Tavosanis
{"title":"Autologous PSC-CMs show long-term engraftment after infarction in non-human primates","authors":"Andrea Tavosanis","doi":"10.1038/s44161-024-00514-z","DOIUrl":"10.1038/s44161-024-00514-z","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"774-774"},"PeriodicalIF":9.4,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-27DOI: 10.1038/s44161-024-00504-1
Salim Abdelilah-Seyfried, Hanjoong Jo
The discovery of the genes causing cerebral cavernous malformation (CCM) initially heralded a fruitful search for etiopathogenic molecular pathways in this rare cerebrovascular disease. Recent studies have identified the relevance of CCM proteins for much more common vascular biology and pathologies.
{"title":"A renaissance of cerebral cavernous malformation proteins in vascular physiology","authors":"Salim Abdelilah-Seyfried, Hanjoong Jo","doi":"10.1038/s44161-024-00504-1","DOIUrl":"10.1038/s44161-024-00504-1","url":null,"abstract":"The discovery of the genes causing cerebral cavernous malformation (CCM) initially heralded a fruitful search for etiopathogenic molecular pathways in this rare cerebrovascular disease. Recent studies have identified the relevance of CCM proteins for much more common vascular biology and pathologies.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 7","pages":"771-773"},"PeriodicalIF":9.4,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141639679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：