Pub Date : 2024-09-18DOI: 10.1038/s44161-024-00542-9
Khanh V. Doan, Timothy S. Luongo, Thato T. Ts’olo, Won Dong Lee, David W. Frederick, Sarmistha Mukherjee, Gabriel K. Adzika, Caroline E. Perry, Ryan B. Gaspar, Nicole Walker, Megan C. Blair, Nicole Bye, James G. Davis, Corey D. Holman, Qingwei Chu, Lin Wang, Joshua D. Rabinowitz, Daniel P. Kelly, Thomas P. Cappola, Kenneth B. Margulies, Joseph A. Baur
Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics. Doan et al. show that loss of cardiac NAD+ is sufficient to drive metabolic derangements, hypertrophic remodeling and lethal arrhythmias in adult mouse hearts, despite maintenance of ejection fraction and bioenergetics.
{"title":"Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics","authors":"Khanh V. Doan, Timothy S. Luongo, Thato T. Ts’olo, Won Dong Lee, David W. Frederick, Sarmistha Mukherjee, Gabriel K. Adzika, Caroline E. Perry, Ryan B. Gaspar, Nicole Walker, Megan C. Blair, Nicole Bye, James G. Davis, Corey D. Holman, Qingwei Chu, Lin Wang, Joshua D. Rabinowitz, Daniel P. Kelly, Thomas P. Cappola, Kenneth B. Margulies, Joseph A. Baur","doi":"10.1038/s44161-024-00542-9","DOIUrl":"10.1038/s44161-024-00542-9","url":null,"abstract":"Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics. Doan et al. show that loss of cardiac NAD+ is sufficient to drive metabolic derangements, hypertrophic remodeling and lethal arrhythmias in adult mouse hearts, despite maintenance of ejection fraction and bioenergetics.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 10","pages":"1236-1248"},"PeriodicalIF":9.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247373","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 : 2024-09-13DOI: 10.1038/s44161-024-00539-4
Kazu Kikuchi
The endocardium is activated immediately after injury and promotes cardiac muscle regeneration by producing growth factors. Research now shows that innate immune signaling is crucial for the regenerative function of the endocardium.
{"title":"Success in heart regeneration depends on endocardial innate immune signaling","authors":"Kazu Kikuchi","doi":"10.1038/s44161-024-00539-4","DOIUrl":"10.1038/s44161-024-00539-4","url":null,"abstract":"The endocardium is activated immediately after injury and promotes cardiac muscle regeneration by producing growth factors. Research now shows that innate immune signaling is crucial for the regenerative function of the endocardium.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1031-1032"},"PeriodicalIF":9.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231135","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 : 2024-09-13DOI: 10.1038/s44161-024-00534-9
Fibromuscular dysplasia (FMD) is a poorly understood blood vessel disorder that affects up to 5% of adults. Using a systems genetics approach, we identified an FMD-associated gene co-expression network that governs vascular cell function and developed a mouse model of FMD that recapitulates certain aspects of the human disease.
{"title":"Identifying a gene-regulatory network that drives fibromuscular dysplasia","authors":"","doi":"10.1038/s44161-024-00534-9","DOIUrl":"10.1038/s44161-024-00534-9","url":null,"abstract":"Fibromuscular dysplasia (FMD) is a poorly understood blood vessel disorder that affects up to 5% of adults. Using a systems genetics approach, we identified an FMD-associated gene co-expression network that governs vascular cell function and developed a mouse model of FMD that recapitulates certain aspects of the human disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1033-1034"},"PeriodicalIF":9.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231159","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 : 2024-09-13DOI: 10.1038/s44161-024-00533-w
Valentina d’Escamard, Daniella Kadian-Dodov, Lijiang Ma, Sizhao Lu, Annette King, Yang Xu, Shouneng Peng, Bhargravi V′Gangula, Yu Zhou, Allison Thomas, Katherine C. Michelis, Emir Bander, Rihab Bouchareb, Adrien Georges, Aya Nomura-Kitabayashi, Robert J. Wiener, Kevin D. Costa, Elena Chepurko, Vadim Chepurko, Marika Fava, Temo Barwari, Anelechi Anyanwu, Farzan Filsoufi, Sander Florman, Nabila Bouatia-Naji, Lukas E. Schmidt, Manuel Mayr, Michael G. Katz, Ke Hao, Mary C. M. Weiser-Evans, Johan L. M. Björkegren, Jeffrey W. Olin, Jason C. Kovacic
Fibromuscular dysplasia (FMD) is a poorly understood disease affecting 3–5% of adult females. The pathobiology of FMD involves arterial lesions of stenosis, dissection, tortuosity, dilation and aneurysm, which can lead to hypertension, stroke, myocardial infarction and even death. Currently, there are no animal models for FMD and few insights as to its pathobiology. In this study, by integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 patients with FMD and 71 matched healthy controls, we inferred 18 gene regulatory co-expression networks, four of which were found to act together as an FMD-associated supernetwork in the arterial wall. After in vivo perturbation of this co-expression supernetwork by selective knockout of a top network key driver, mice developed arterial dilation, a hallmark of FMD. Molecular studies indicated that this supernetwork governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. These studies illuminate the complex causal mechanisms of FMD and suggest a potential therapeutic avenue for this challenging disease. By integrating DNA genotype and RNA sequencing data from human samples, d’Escamard et al. identify a gene regulatory co-expression supernetwork that plays an important role in fibromuscular dysplasia, a poorly understood disease affecting 3–5% of adult females.
{"title":"Integrative gene regulatory network analysis discloses key driver genes of fibromuscular dysplasia","authors":"Valentina d’Escamard, Daniella Kadian-Dodov, Lijiang Ma, Sizhao Lu, Annette King, Yang Xu, Shouneng Peng, Bhargravi V′Gangula, Yu Zhou, Allison Thomas, Katherine C. Michelis, Emir Bander, Rihab Bouchareb, Adrien Georges, Aya Nomura-Kitabayashi, Robert J. Wiener, Kevin D. Costa, Elena Chepurko, Vadim Chepurko, Marika Fava, Temo Barwari, Anelechi Anyanwu, Farzan Filsoufi, Sander Florman, Nabila Bouatia-Naji, Lukas E. Schmidt, Manuel Mayr, Michael G. Katz, Ke Hao, Mary C. M. Weiser-Evans, Johan L. M. Björkegren, Jeffrey W. Olin, Jason C. Kovacic","doi":"10.1038/s44161-024-00533-w","DOIUrl":"10.1038/s44161-024-00533-w","url":null,"abstract":"Fibromuscular dysplasia (FMD) is a poorly understood disease affecting 3–5% of adult females. The pathobiology of FMD involves arterial lesions of stenosis, dissection, tortuosity, dilation and aneurysm, which can lead to hypertension, stroke, myocardial infarction and even death. Currently, there are no animal models for FMD and few insights as to its pathobiology. In this study, by integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 patients with FMD and 71 matched healthy controls, we inferred 18 gene regulatory co-expression networks, four of which were found to act together as an FMD-associated supernetwork in the arterial wall. After in vivo perturbation of this co-expression supernetwork by selective knockout of a top network key driver, mice developed arterial dilation, a hallmark of FMD. Molecular studies indicated that this supernetwork governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. These studies illuminate the complex causal mechanisms of FMD and suggest a potential therapeutic avenue for this challenging disease. By integrating DNA genotype and RNA sequencing data from human samples, d’Escamard et al. identify a gene regulatory co-expression supernetwork that plays an important role in fibromuscular dysplasia, a poorly understood disease affecting 3–5% of adult females.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1098-1122"},"PeriodicalIF":9.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231142","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 : 2024-09-13DOI: 10.1038/s44161-024-00538-5
Pinelopi Goumenaki, Stefan Günther, Khrievono Kikhi, Mario Looso, Rubén Marín-Juez, Didier Y. R. Stainier
The innate immune response is triggered rapidly after injury and its spatiotemporal dynamics are critical for regeneration; however, many questions remain about its exact role. Here we show that MyD88, a key component of the innate immune response, controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. We find in cryoinjured myd88−/− ventricles a significant reduction in neutrophil and macrophage numbers and the expansion of a collagen-rich endocardial population. Further analyses reveal compromised PI3K/AKT pathway activation in the myd88−/− endocardium and increased myofibroblasts and scarring. Notably, endothelial-specific overexpression of myd88 reverses these neutrophil, fibrotic and scarring phenotypes. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88 signaling pathway, and using loss-of-function and gain-of-function tools, we show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration. Goumenaki et al. uncover that during zebrafish cardiac regeneration, MyD88 signaling promotes the inflammatory response to injury and attenuates the endocardial-mediated fibrotic response.
{"title":"The innate immune regulator MyD88 dampens fibrosis during zebrafish heart regeneration","authors":"Pinelopi Goumenaki, Stefan Günther, Khrievono Kikhi, Mario Looso, Rubén Marín-Juez, Didier Y. R. Stainier","doi":"10.1038/s44161-024-00538-5","DOIUrl":"10.1038/s44161-024-00538-5","url":null,"abstract":"The innate immune response is triggered rapidly after injury and its spatiotemporal dynamics are critical for regeneration; however, many questions remain about its exact role. Here we show that MyD88, a key component of the innate immune response, controls not only the inflammatory but also the fibrotic response during zebrafish cardiac regeneration. We find in cryoinjured myd88−/− ventricles a significant reduction in neutrophil and macrophage numbers and the expansion of a collagen-rich endocardial population. Further analyses reveal compromised PI3K/AKT pathway activation in the myd88−/− endocardium and increased myofibroblasts and scarring. Notably, endothelial-specific overexpression of myd88 reverses these neutrophil, fibrotic and scarring phenotypes. Mechanistically, we identify the endocardial-derived chemokine gene cxcl18b as a target of the MyD88 signaling pathway, and using loss-of-function and gain-of-function tools, we show that it controls neutrophil recruitment. Altogether, these findings shed light on the pivotal role of MyD88 in modulating inflammation and fibrosis during tissue regeneration. Goumenaki et al. uncover that during zebrafish cardiac regeneration, MyD88 signaling promotes the inflammatory response to injury and attenuates the endocardial-mediated fibrotic response.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1158-1176"},"PeriodicalIF":9.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00538-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231130","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 : 2024-09-10DOI: 10.1038/s44161-024-00541-w
Gerburg Schwaerzer
{"title":"Macrophages and hematopoietic stem cells teach us that sharing is caring","authors":"Gerburg Schwaerzer","doi":"10.1038/s44161-024-00541-w","DOIUrl":"10.1038/s44161-024-00541-w","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1020-1020"},"PeriodicalIF":9.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192436","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 : 2024-09-04DOI: 10.1038/s44161-024-00523-y
Christian Park, Kyung In Baek, Hanjoong Jo
Atherosclerosis occurs in arterial regions exposed to disturbed flow, where endothelial expression of flow-sensitive, atheroprotective genes such as KLF2 and KLF4 is reduced. Protecting the endothelial expression of KLF2 and KLF4 from inhibitory factors could be a therapeutic approach to prevent vascular inflammation and atherosclerosis.
{"title":"Saving KLF2/4 from γ-protocadherin to reduce vascular inflammation and atherosclerosis","authors":"Christian Park, Kyung In Baek, Hanjoong Jo","doi":"10.1038/s44161-024-00523-y","DOIUrl":"10.1038/s44161-024-00523-y","url":null,"abstract":"Atherosclerosis occurs in arterial regions exposed to disturbed flow, where endothelial expression of flow-sensitive, atheroprotective genes such as KLF2 and KLF4 is reduced. Protecting the endothelial expression of KLF2 and KLF4 from inhibitory factors could be a therapeutic approach to prevent vascular inflammation and atherosclerosis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1021-1023"},"PeriodicalIF":9.4,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134665","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 : 2024-09-04DOI: 10.1038/s44161-024-00522-z
Divyesh Joshi, Brian G. Coon, Raja Chakraborty, Hanqiang Deng, Ziyu Yang, Muhammad Usman Babar, Pablo Fernandez-Tussy, Emily Meredith, John Attanasio, Nikhil Joshi, James G. Traylor Jr., Anthony Wayne Orr, Carlos Fernandez-Hernando, Stephania Libreros, Martin A. Schwartz
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Laminar shear stress from blood flow, sensed by vascular endothelial cells, protects from ASCVD by upregulating the transcription factors KLF2 and KLF4, which induces an anti-inflammatory program that promotes vascular resilience. Here we identify clustered γ-protocadherins as therapeutically targetable, potent KLF2 and KLF4 suppressors whose upregulation contributes to ASCVD. Mechanistic studies show that γ-protocadherin cleavage results in translocation of the conserved intracellular domain to the nucleus where it physically associates with and suppresses signaling by the Notch intracellular domain. γ-Protocadherins are elevated in human ASCVD endothelium; their genetic deletion or antibody blockade protects from ASCVD in mice without detectably compromising host defense against bacterial or viral infection. These results elucidate a fundamental mechanism of vascular inflammation and reveal a method to target the endothelium rather than the immune system as a protective strategy in ASCVD. Joshi et al. show that γ-protocadherins suppress the anti-inflammatory KLF2 and KLF4 pathway and that targeting them is a viable therapeutic strategy to protect against atherosclerosis.
{"title":"Endothelial γ-protocadherins inhibit KLF2 and KLF4 to promote atherosclerosis","authors":"Divyesh Joshi, Brian G. Coon, Raja Chakraborty, Hanqiang Deng, Ziyu Yang, Muhammad Usman Babar, Pablo Fernandez-Tussy, Emily Meredith, John Attanasio, Nikhil Joshi, James G. Traylor Jr., Anthony Wayne Orr, Carlos Fernandez-Hernando, Stephania Libreros, Martin A. Schwartz","doi":"10.1038/s44161-024-00522-z","DOIUrl":"10.1038/s44161-024-00522-z","url":null,"abstract":"Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Laminar shear stress from blood flow, sensed by vascular endothelial cells, protects from ASCVD by upregulating the transcription factors KLF2 and KLF4, which induces an anti-inflammatory program that promotes vascular resilience. Here we identify clustered γ-protocadherins as therapeutically targetable, potent KLF2 and KLF4 suppressors whose upregulation contributes to ASCVD. Mechanistic studies show that γ-protocadherin cleavage results in translocation of the conserved intracellular domain to the nucleus where it physically associates with and suppresses signaling by the Notch intracellular domain. γ-Protocadherins are elevated in human ASCVD endothelium; their genetic deletion or antibody blockade protects from ASCVD in mice without detectably compromising host defense against bacterial or viral infection. These results elucidate a fundamental mechanism of vascular inflammation and reveal a method to target the endothelium rather than the immune system as a protective strategy in ASCVD. Joshi et al. show that γ-protocadherins suppress the anti-inflammatory KLF2 and KLF4 pathway and that targeting them is a viable therapeutic strategy to protect against atherosclerosis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1035-1048"},"PeriodicalIF":9.4,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00522-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134664","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}
The neonatal mammalian heart can regenerate following injury through cardiomyocyte proliferation but loses this potential by postnatal day 7. Stimulating adult cardiomyocytes to reenter the cell cycle remains unclear. Here we show that cardiomyocyte proliferation depends on its metabolic state. Given the connection between the tricarboxylic acid cycle and cell proliferation, we analyzed these metabolites in mouse hearts from postnatal day 0.5 to day 7 and found that α-ketoglutarate ranked highest among the decreased metabolites. Injection of α-ketoglutarate extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-ketoglutarate levels. Mechanistically, α-ketoglutarate decreases H3K27me3 deposition at the promoters of cell cycle genes in cardiomyocytes. Thus, α-ketoglutarate promotes cardiomyocyte proliferation through JMJD3-dependent demethylation, offering a potential approach for treating myocardial infarction. Yu Shi et al. show that the citric acid cycle metabolite α-ketoglutarate promotes cardiomyocyte proliferation during heart development and promotes heart regeneration after myocardial infarction.
{"title":"α-Ketoglutarate promotes cardiomyocyte proliferation and heart regeneration after myocardial infarction","authors":"Yu Shi, Miao Tian, Xiaofang Zhao, Luxun Tang, Feng Wang, Hao Wu, Qiao Liao, Hongmei Ren, Wenbin Fu, Shuo Zheng, Pedro A. Jose, Liangpeng Li, Chunyu Zeng","doi":"10.1038/s44161-024-00531-y","DOIUrl":"10.1038/s44161-024-00531-y","url":null,"abstract":"The neonatal mammalian heart can regenerate following injury through cardiomyocyte proliferation but loses this potential by postnatal day 7. Stimulating adult cardiomyocytes to reenter the cell cycle remains unclear. Here we show that cardiomyocyte proliferation depends on its metabolic state. Given the connection between the tricarboxylic acid cycle and cell proliferation, we analyzed these metabolites in mouse hearts from postnatal day 0.5 to day 7 and found that α-ketoglutarate ranked highest among the decreased metabolites. Injection of α-ketoglutarate extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-ketoglutarate levels. Mechanistically, α-ketoglutarate decreases H3K27me3 deposition at the promoters of cell cycle genes in cardiomyocytes. Thus, α-ketoglutarate promotes cardiomyocyte proliferation through JMJD3-dependent demethylation, offering a potential approach for treating myocardial infarction. Yu Shi et al. show that the citric acid cycle metabolite α-ketoglutarate promotes cardiomyocyte proliferation during heart development and promotes heart regeneration after myocardial infarction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 9","pages":"1083-1097"},"PeriodicalIF":9.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142121286","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}
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