Pub Date : 2024-11-19DOI: 10.1038/s44161-024-00575-0
Ziyang Liu, Ali Ajam, Jun Huang, Yu-Sheng Yeh, Babak Razani
{"title":"Glutamine-glutamate imbalance in the pathogenesis of cardiovascular disease.","authors":"Ziyang Liu, Ali Ajam, Jun Huang, Yu-Sheng Yeh, Babak Razani","doi":"10.1038/s44161-024-00575-0","DOIUrl":"https://doi.org/10.1038/s44161-024-00575-0","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677984","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 : 2024-11-19DOI: 10.1038/s44161-024-00566-1
Florent Murcy, Coraline Borowczyk, Samuel Gourion-Arsiquaud, Stéphanie Torrino, Nessrine Ouahrouche, Thibault Barouillet, Sébastien Dussaud, Marie Couralet, Nathalie Vaillant, Johanna Merlin, Alexandre Berquand, Minna U Kaikkonen, Robyn L McClelland, William Tressel, James Stein, Edward B Thorp, Thomas Bertero, Pascal Barbry, Béatrice Bailly-Maitre, Emmanuel L Gautier, Minna K Karjalainen, Johannes Kettunen, Laurent Duca, Steven Shea, Laurent Yvan-Charvet
Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common among patients with cardiovascular diseases, but the underlying mechanisms remain largely unknown. Using the human MESA cohort, here we show that plasma glutamine-glutamate ratio is an independent risk factor for carotid plaque progression. Mice deficient in glutaminase-2 (Gls2), the enzyme that mediates hepatic glutaminolysis, developed accelerated atherosclerosis and susceptibility to catastrophic cardiac events, while Gls2 overexpression partially protected from disease progression. High-throughput transcriptional profiling and high-resolution structural biology imaging of aortas showed that Gls2 deficiency perturbed extracellular matrix composition and increased vessel stiffness. This results from an imbalance of glutamine- and glutamate-dependent cross-linked proteins within atherosclerotic lesions and cellular remodeling of plaques. Thus, hepatic glutaminolysis functions as a potent regulator of glutamine homeostasis, which affects the aortic wall structure during atherosclerotic plaque progression.
{"title":"GLS2 links glutamine metabolism and atherosclerosis by remodeling artery walls.","authors":"Florent Murcy, Coraline Borowczyk, Samuel Gourion-Arsiquaud, Stéphanie Torrino, Nessrine Ouahrouche, Thibault Barouillet, Sébastien Dussaud, Marie Couralet, Nathalie Vaillant, Johanna Merlin, Alexandre Berquand, Minna U Kaikkonen, Robyn L McClelland, William Tressel, James Stein, Edward B Thorp, Thomas Bertero, Pascal Barbry, Béatrice Bailly-Maitre, Emmanuel L Gautier, Minna K Karjalainen, Johannes Kettunen, Laurent Duca, Steven Shea, Laurent Yvan-Charvet","doi":"10.1038/s44161-024-00566-1","DOIUrl":"https://doi.org/10.1038/s44161-024-00566-1","url":null,"abstract":"<p><p>Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common among patients with cardiovascular diseases, but the underlying mechanisms remain largely unknown. Using the human MESA cohort, here we show that plasma glutamine-glutamate ratio is an independent risk factor for carotid plaque progression. Mice deficient in glutaminase-2 (Gls2), the enzyme that mediates hepatic glutaminolysis, developed accelerated atherosclerosis and susceptibility to catastrophic cardiac events, while Gls2 overexpression partially protected from disease progression. High-throughput transcriptional profiling and high-resolution structural biology imaging of aortas showed that Gls2 deficiency perturbed extracellular matrix composition and increased vessel stiffness. This results from an imbalance of glutamine- and glutamate-dependent cross-linked proteins within atherosclerotic lesions and cellular remodeling of plaques. Thus, hepatic glutaminolysis functions as a potent regulator of glutamine homeostasis, which affects the aortic wall structure during atherosclerotic plaque progression.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677982","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 : 2024-11-12DOI: 10.1038/s44161-024-00549-2
In newborn mice, after a neonatal cardiac infarction, cells derived from the ventricular trabeculae participate in the repair of the contractile myocardium, but this process results in excessive production of immature Purkinje fibers that form a hyperplastic network and lead to altered ventricular conduction.
{"title":"Cardiac regeneration leads to altered Purkinje fiber network and ventricular conduction","authors":"","doi":"10.1038/s44161-024-00549-2","DOIUrl":"10.1038/s44161-024-00549-2","url":null,"abstract":"In newborn mice, after a neonatal cardiac infarction, cells derived from the ventricular trabeculae participate in the repair of the contractile myocardium, but this process results in excessive production of immature Purkinje fibers that form a hyperplastic network and lead to altered ventricular conduction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 11","pages":"1272-1273"},"PeriodicalIF":9.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142600841","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}
Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Krüppel-like factor 9 (Klf9) is dysregulated in human and rodent cardiomyopathy. Both global and cardiac-specific Klf9-deficient mice displayed hypertrophic cardiomyopathy. Klf9 knockout led to mitochondrial disarray and fragmentation, impairing mitochondrial respiratory function in cardiomyocytes. Furthermore, cardiac Klf9 deficiency inhibited mitophagy, thereby causing accumulation of dysfunctional mitochondria and acceleration of heart failure in response to angiotensin II treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function. Mechanistically, Klf9 knockout decreased the expression of PGC-1α and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 controlled the expression of Mfn2, thereby regulating mitochondrial dynamics and mitophagy. Finally, adeno-associated virus–mediated Mfn2 rescue in Klf9-CKO hearts improved cardiac mitochondrial and systolic function. Thus, Klf9 integrates cardiac energy metabolism, mitochondrial dynamics and mitophagy. Modulating Klf9 activity may have therapeutic potential in the treatment of heart failure. L. Zhang, M. Zhang, Huang et al. show that Klf9 regulated PGC-1α and Mfn2 expression, contributing to mitochondrial energy metabolism and dynamic regulation, promoting mitophagy, improving cardiac function and revealing a potential therapeutic target.
{"title":"Klf9 is essential for cardiac mitochondrial homeostasis","authors":"Lei Zhang, Menglin Zhang, Jinlong Huang, Jincan Huang, Yujie Zhang, Yinliang Zhang, Houzao Chen, Cuizhe Wang, Xiangwen Xi, Heng Fan, Jikui Wang, Dingsheng Jiang, Jinwei Tian, Jun Zhang, Yongsheng Chang","doi":"10.1038/s44161-024-00561-6","DOIUrl":"10.1038/s44161-024-00561-6","url":null,"abstract":"Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Krüppel-like factor 9 (Klf9) is dysregulated in human and rodent cardiomyopathy. Both global and cardiac-specific Klf9-deficient mice displayed hypertrophic cardiomyopathy. Klf9 knockout led to mitochondrial disarray and fragmentation, impairing mitochondrial respiratory function in cardiomyocytes. Furthermore, cardiac Klf9 deficiency inhibited mitophagy, thereby causing accumulation of dysfunctional mitochondria and acceleration of heart failure in response to angiotensin II treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function. Mechanistically, Klf9 knockout decreased the expression of PGC-1α and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 controlled the expression of Mfn2, thereby regulating mitochondrial dynamics and mitophagy. Finally, adeno-associated virus–mediated Mfn2 rescue in Klf9-CKO hearts improved cardiac mitochondrial and systolic function. Thus, Klf9 integrates cardiac energy metabolism, mitochondrial dynamics and mitophagy. Modulating Klf9 activity may have therapeutic potential in the treatment of heart failure. L. Zhang, M. Zhang, Huang et al. show that Klf9 regulated PGC-1α and Mfn2 expression, contributing to mitochondrial energy metabolism and dynamic regulation, promoting mitophagy, improving cardiac function and revealing a potential therapeutic target.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 11","pages":"1318-1336"},"PeriodicalIF":9.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142600842","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 : 2024-11-08DOI: 10.1038/s44161-024-00560-7
Máté G. Kiss, Oren Cohen, Cameron S. McAlpine, Filip K. Swirski
Sleep is a fundamental requirement of life and is integral to health. Deviation from optimal sleep associates with numerous diseases including those of the cardiovascular system. Studies, spanning animal models to humans, show that insufficient, disrupted or inconsistent sleep contribute to poor cardiovascular health by disrupting body systems. Fundamental experiments have begun to uncover the molecular and cellular links between sleep and heart health while large-scale human studies have associated sleep with cardiovascular outcomes in diverse populations. Here, we review preclinical and clinical findings that demonstrate how sleep influences the autonomic nervous, metabolic and immune systems to affect atherosclerotic cardiovascular disease. Kiss et al. review preclinical and clinical evidence illustrating how sleep impacts the nervous, metabolic and immune systems, ultimately influencing the development and progression of atherosclerotic cardiovascular disease.
{"title":"Influence of sleep on physiological systems in atherosclerosis","authors":"Máté G. Kiss, Oren Cohen, Cameron S. McAlpine, Filip K. Swirski","doi":"10.1038/s44161-024-00560-7","DOIUrl":"10.1038/s44161-024-00560-7","url":null,"abstract":"Sleep is a fundamental requirement of life and is integral to health. Deviation from optimal sleep associates with numerous diseases including those of the cardiovascular system. Studies, spanning animal models to humans, show that insufficient, disrupted or inconsistent sleep contribute to poor cardiovascular health by disrupting body systems. Fundamental experiments have begun to uncover the molecular and cellular links between sleep and heart health while large-scale human studies have associated sleep with cardiovascular outcomes in diverse populations. Here, we review preclinical and clinical findings that demonstrate how sleep influences the autonomic nervous, metabolic and immune systems to affect atherosclerotic cardiovascular disease. Kiss et al. review preclinical and clinical evidence illustrating how sleep impacts the nervous, metabolic and immune systems, ultimately influencing the development and progression of atherosclerotic cardiovascular disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 11","pages":"1284-1300"},"PeriodicalIF":9.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142600866","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 : 2024-11-01DOI: 10.1038/s44161-024-00558-1
Julia C. Isbister, Rafik Tadros, Hariharan Raju, Christopher Semsarian
The inherited cardiomyopathies exhibit a broad spectrum of disease, with some patients remaining asymptomatic throughout life, while, for others, the first symptom of disease is sudden cardiac death at a young age. The risk of malignant ventricular arrhythmia in these conditions has traditionally been linked to the degree of structural myocardial abnormalities and functional impairment. However, recent advances in genetic testing and knowledge of the genetic basis of the diseases have led to the identification of concealed cardiomyopathy, in which sudden cardiac arrest or sudden cardiac death occurs in the absence of observable clinical features of cardiomyopathy, with a diagnosis being made only after the identification of a causative genetic variant. Increased awareness of concealed cardiomyopathy, a better understanding of mechanisms of arrhythmia and identification of risk modulators will be vital to improve care for families with concealed cardiomyopathy. Isbister et al. review the recent advances in understanding the genetic basis of the diseases that have led to the identification of concealed cardiomyopathy, where sudden cardiac arrest or death occurs even in the absence of observable clinical features of cardiomyopathy.
{"title":"Concealed cardiomyopathy as an emerging cause of sudden cardiac arrest and sudden cardiac death","authors":"Julia C. Isbister, Rafik Tadros, Hariharan Raju, Christopher Semsarian","doi":"10.1038/s44161-024-00558-1","DOIUrl":"10.1038/s44161-024-00558-1","url":null,"abstract":"The inherited cardiomyopathies exhibit a broad spectrum of disease, with some patients remaining asymptomatic throughout life, while, for others, the first symptom of disease is sudden cardiac death at a young age. The risk of malignant ventricular arrhythmia in these conditions has traditionally been linked to the degree of structural myocardial abnormalities and functional impairment. However, recent advances in genetic testing and knowledge of the genetic basis of the diseases have led to the identification of concealed cardiomyopathy, in which sudden cardiac arrest or sudden cardiac death occurs in the absence of observable clinical features of cardiomyopathy, with a diagnosis being made only after the identification of a causative genetic variant. Increased awareness of concealed cardiomyopathy, a better understanding of mechanisms of arrhythmia and identification of risk modulators will be vital to improve care for families with concealed cardiomyopathy. Isbister et al. review the recent advances in understanding the genetic basis of the diseases that have led to the identification of concealed cardiomyopathy, where sudden cardiac arrest or death occurs even in the absence of observable clinical features of cardiomyopathy.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 11","pages":"1274-1283"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564837","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 : 2024-11-01DOI: 10.1038/s44161-024-00550-9
Sajeth Dinakaran, Sima Qutaina, Haitian Zhao, Yuefeng Tang, Zhimin Wang, Santiago Ruiz, Aya Nomura-Kitabayashi, Christine N. Metz, Helen M. Arthur, Stryder M. Meadows, Lionel Blanc, Marie E. Faughnan, Philippe Marambaud
Increased endothelial cell proliferation is a hallmark of arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). Here, we report a cyclin-dependent kinase 6 (CDK6)-driven mechanism of cell cycle deregulation involved in endothelial cell proliferation and HHT pathology. Specifically, endothelial cells from the livers of HHT mice bypassed the G1/S checkpoint and progressed through the cell cycle at an accelerated pace. Phosphorylated retinoblastoma (pRB1)—a marker of G1/S transition through the restriction point—accumulated in endothelial cells from retinal AVMs of HHT mice and endothelial cells from skin telangiectasia samples from HHT patients. Mechanistically, inhibition of activin receptor-like kinase 1 signaling increased key restriction point mediators, and treatment with the CDK4/6 inhibitors palbociclib or ribociclib blocked increases in pRB1 and retinal AVMs in HHT mice. Palbociclib also improved vascular pathology in the brain and liver, and slowed cell cycle progression in endothelial cells and endothelial cell proliferation. Endothelial cell-specific deletion of CDK6 was sufficient to protect HHT mice from AVM pathology. Thus, clinically approved CDK4/6 inhibitors might have the potential to be repurposed for HHT. Dinakaran et al. show that arteriovenous malformations in hereditary hemorrhagic telangiectasia are caused by CDK6-mediated cell cycle acceleration in response to BMP9/BMP10 inhibition and that CDK4/6 inhibitors can prevent the development of the disease.
{"title":"CDK6-mediated endothelial cell cycle acceleration drives arteriovenous malformations in hereditary hemorrhagic telangiectasia","authors":"Sajeth Dinakaran, Sima Qutaina, Haitian Zhao, Yuefeng Tang, Zhimin Wang, Santiago Ruiz, Aya Nomura-Kitabayashi, Christine N. Metz, Helen M. Arthur, Stryder M. Meadows, Lionel Blanc, Marie E. Faughnan, Philippe Marambaud","doi":"10.1038/s44161-024-00550-9","DOIUrl":"10.1038/s44161-024-00550-9","url":null,"abstract":"Increased endothelial cell proliferation is a hallmark of arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). Here, we report a cyclin-dependent kinase 6 (CDK6)-driven mechanism of cell cycle deregulation involved in endothelial cell proliferation and HHT pathology. Specifically, endothelial cells from the livers of HHT mice bypassed the G1/S checkpoint and progressed through the cell cycle at an accelerated pace. Phosphorylated retinoblastoma (pRB1)—a marker of G1/S transition through the restriction point—accumulated in endothelial cells from retinal AVMs of HHT mice and endothelial cells from skin telangiectasia samples from HHT patients. Mechanistically, inhibition of activin receptor-like kinase 1 signaling increased key restriction point mediators, and treatment with the CDK4/6 inhibitors palbociclib or ribociclib blocked increases in pRB1 and retinal AVMs in HHT mice. Palbociclib also improved vascular pathology in the brain and liver, and slowed cell cycle progression in endothelial cells and endothelial cell proliferation. Endothelial cell-specific deletion of CDK6 was sufficient to protect HHT mice from AVM pathology. Thus, clinically approved CDK4/6 inhibitors might have the potential to be repurposed for HHT. Dinakaran et al. show that arteriovenous malformations in hereditary hemorrhagic telangiectasia are caused by CDK6-mediated cell cycle acceleration in response to BMP9/BMP10 inhibition and that CDK4/6 inhibitors can prevent the development of the disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 11","pages":"1301-1317"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564775","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 : 2024-11-01DOI: 10.1038/s44161-024-00557-2
Nicolas Ricard, Sabine Bailly
Arteriovenous malformations are the hallmark of patients with hereditary hemorrhagic telangectasia. Research now finds that this could be due to endothelial cell-cycle acceleration via CDK6. These results could suggest repurposing CDK6 inhibitors for this disorder.
{"title":"Inhibition of endothelial cell proliferation as a potential therapeutic approach in hereditary hemorrhagic telangectasia","authors":"Nicolas Ricard, Sabine Bailly","doi":"10.1038/s44161-024-00557-2","DOIUrl":"10.1038/s44161-024-00557-2","url":null,"abstract":"Arteriovenous malformations are the hallmark of patients with hereditary hemorrhagic telangectasia. Research now finds that this could be due to endothelial cell-cycle acceleration via CDK6. These results could suggest repurposing CDK6 inhibitors for this disorder.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 11","pages":"1267-1269"},"PeriodicalIF":9.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564922","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 : 2024-10-25DOI: 10.1038/s44161-024-00559-0
Jennifer J. Hill
Glycoprotein non-metastatic melanoma protein B (GPNMB) is produced by macrophages and mediates cardiac repair through direct interaction with an orphan G-protein-coupled receptor, GPR39.
糖蛋白非转移性黑色素瘤蛋白 B（GPNMB）由巨噬细胞产生，通过与孤儿 G 蛋白偶联受体 GPR39 直接相互作用，介导心脏修复。
{"title":"Macrophage GPNMB-mediated cardiac repair","authors":"Jennifer J. Hill","doi":"10.1038/s44161-024-00559-0","DOIUrl":"10.1038/s44161-024-00559-0","url":null,"abstract":"Glycoprotein non-metastatic melanoma protein B (GPNMB) is produced by macrophages and mediates cardiac repair through direct interaction with an orphan G-protein-coupled receptor, GPR39.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 11","pages":"1270-1271"},"PeriodicalIF":9.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514175","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 : 2024-10-25DOI: 10.1038/s44161-024-00555-4
Sivakumar Ramadoss, Juan Qin, Bo Tao, Nathan E. Thomas, Edward Cao, Rimao Wu, Daniel R. Sandoval, Ann Piermatteo, Kaare V. Grunddal, Feiyang Ma, Shen Li, Baiming Sun, Yonggang Zhou, Jijun Wan, Matteo Pellegrini, Birgitte Holst, Aldons J. Lusis, Philip L.S.M. Gordts, Arjun Deb
Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling. Ramadoss et al. show that bone-marrow-derived macrophages contribute to heart repair following myocardial infarction by secreting GPNMB, which binds to the orphan receptor GPR39 to improve myocyte contractility and reduce fibroblast activation.
{"title":"Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair","authors":"Sivakumar Ramadoss, Juan Qin, Bo Tao, Nathan E. Thomas, Edward Cao, Rimao Wu, Daniel R. Sandoval, Ann Piermatteo, Kaare V. Grunddal, Feiyang Ma, Shen Li, Baiming Sun, Yonggang Zhou, Jijun Wan, Matteo Pellegrini, Birgitte Holst, Aldons J. Lusis, Philip L.S.M. Gordts, Arjun Deb","doi":"10.1038/s44161-024-00555-4","DOIUrl":"10.1038/s44161-024-00555-4","url":null,"abstract":"Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling. Ramadoss et al. show that bone-marrow-derived macrophages contribute to heart repair following myocardial infarction by secreting GPNMB, which binds to the orphan receptor GPR39 to improve myocyte contractility and reduce fibroblast activation.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 11","pages":"1356-1373"},"PeriodicalIF":9.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516782","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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