Nature cardiovascular research最新文献_第8页

Klf9 is essential for cardiac mitochondrial homeostasis Klf9 对心脏线粒体的稳态至关重要

IF 9.4

Nature cardiovascular research Pub Date : 2024-11-08 DOI: 10.1038/s44161-024-00561-6

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

{"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}

引用次数: 0

Influence of sleep on physiological systems in atherosclerosis 睡眠对动脉粥样硬化生理系统的影响

IF 9.4

Nature cardiovascular research Pub Date : 2024-11-08 DOI: 10.1038/s44161-024-00560-7

Máté G. Kiss, Oren Cohen, Cameron S. McAlpine, Filip K. Swirski

引用次数: 0

Concealed cardiomyopathy as an emerging cause of sudden cardiac arrest and sudden cardiac death 隐匿性心肌病是导致心脏骤停和心脏性猝死的一个新原因。

IF 9.4

Nature cardiovascular research Pub Date : 2024-11-01 DOI: 10.1038/s44161-024-00558-1

Julia C. Isbister, Rafik Tadros, Hariharan Raju, Christopher Semsarian

{"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}

引用次数: 0

CDK6-mediated endothelial cell cycle acceleration drives arteriovenous malformations in hereditary hemorrhagic telangiectasia CDK6介导的内皮细胞周期加速驱动遗传性出血性毛细血管扩张症中的动静脉畸形。

IF 9.4

Nature cardiovascular research Pub Date : 2024-11-01 DOI: 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

{"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}

引用次数: 0

Inhibition of endothelial cell proliferation as a potential therapeutic approach in hereditary hemorrhagic telangectasia 将抑制内皮细胞增殖作为遗传性出血性毛细血管扩张症的一种潜在治疗方法。

IF 9.4

Nature cardiovascular research Pub Date : 2024-11-01 DOI: 10.1038/s44161-024-00557-2

Nicolas Ricard, Sabine Bailly

引用次数: 0

Macrophage GPNMB-mediated cardiac repair 巨噬细胞 GPNMB 介导的心脏修复

IF 9.4

Nature cardiovascular research Pub Date : 2024-10-25 DOI: 10.1038/s44161-024-00559-0

Jennifer J. Hill

引用次数: 0

Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair 骨髓巨噬细胞衍生的 GPNMB 蛋白与孤儿受体 GPR39 结合，在心脏修复中发挥关键作用。

IF 9.4

Nature cardiovascular research Pub Date : 2024-10-25 DOI: 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

{"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}

引用次数: 0

Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury 缺血性心脏损伤后，常驻心脏巨噬细胞的缺氧感知调节单核细胞的命运分化。

IF 9.4

Nature cardiovascular research Pub Date : 2024-10-21 DOI: 10.1038/s44161-024-00553-6

Farid F. Kadyrov, Andrew L. Koenig, Junedh M. Amrute, Hao Dun, Wenjun Li, Carla J. Weinheimer, Jessica M. Nigro, Attila Kovacs, Andrea L. Bredemeyer, Steven Yang, Shibali Das, Vinay R. Penna, Alekhya Parvathaneni, Lulu Lai, Niklas Hartmann, Benjamin J. Kopecky, Daniel Kreisel, Kory J. Lavine

{"title":"Hypoxia sensing in resident cardiac macrophages regulates monocyte fate specification following ischemic heart injury","authors":"Farid F. Kadyrov, Andrew L. Koenig, Junedh M. Amrute, Hao Dun, Wenjun Li, Carla J. Weinheimer, Jessica M. Nigro, Attila Kovacs, Andrea L. Bredemeyer, Steven Yang, Shibali Das, Vinay R. Penna, Alekhya Parvathaneni, Lulu Lai, Niklas Hartmann, Benjamin J. Kopecky, Daniel Kreisel, Kory J. Lavine","doi":"10.1038/s44161-024-00553-6","DOIUrl":"10.1038/s44161-024-00553-6","url":null,"abstract":"Myocardial infarction initiates cardiac remodeling and is central to heart failure pathogenesis. Following myocardial ischemia–reperfusion injury, monocytes enter the heart and differentiate into diverse subpopulations of macrophages. Here we show that deletion of Hif1α, a hypoxia response transcription factor, in resident cardiac macrophages led to increased remodeling and overrepresentation of macrophages expressing arginase 1 (Arg1). Arg1+ macrophages displayed an inflammatory gene signature and may represent an intermediate state of monocyte differentiation. Lineage tracing of Arg1+ macrophages revealed a monocyte differentiation trajectory consisting of multiple transcriptionally distinct states. We further showed that deletion of Hif1α in resident cardiac macrophages resulted in arrested progression through this trajectory and accumulation of an inflammatory intermediate state marked by persistent Arg1 expression. Depletion of the Arg1+ trajectory accelerated cardiac remodeling following ischemic injury. Our findings unveil distinct trajectories of monocyte differentiation and identify hypoxia sensing as an important determinant of monocyte differentiation following myocardial infarction. Kadyrov et al. reveal that the hypoxia sensing through HIF1A is an important regulator of monocyte-derived macrophage differentiation, which determines the extent of inflammation and cardiac remodeling after injury.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 11","pages":"1337-1355"},"PeriodicalIF":9.4,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482515","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}

引用次数: 0

CCL2-mediated endothelial injury drives cardiac dysfunction in long COVID CCL2 介导的内皮损伤导致长 COVID 的心脏功能障碍

IF 9.4

Nature cardiovascular research Pub Date : 2024-10-14 DOI: 10.1038/s44161-024-00543-8

Dilip Thomas, Chikage Noishiki, Sadhana Gaddam, David Wu, Amit Manhas, Yu Liu, Dipti Tripathi, Nimish Kathale, Shaunak S. Adkar, Jaishree Garhyan, Chun Liu, Baohui Xu, Elsie G. Ross, Ronald L. Dalman, Kevin C. Wang, Anthony E. Oro, Karim Sallam, Jason T. Lee, Joseph C. Wu, Nazish Sayed

{"title":"CCL2-mediated endothelial injury drives cardiac dysfunction in long COVID","authors":"Dilip Thomas, Chikage Noishiki, Sadhana Gaddam, David Wu, Amit Manhas, Yu Liu, Dipti Tripathi, Nimish Kathale, Shaunak S. Adkar, Jaishree Garhyan, Chun Liu, Baohui Xu, Elsie G. Ross, Ronald L. Dalman, Kevin C. Wang, Anthony E. Oro, Karim Sallam, Jason T. Lee, Joseph C. Wu, Nazish Sayed","doi":"10.1038/s44161-024-00543-8","DOIUrl":"10.1038/s44161-024-00543-8","url":null,"abstract":"Evidence linking the endothelium to cardiac injury in long coronavirus disease (COVID) is well documented, but the underlying mechanisms remain unknown. Here we show that cytokines released by endothelial cells (ECs) contribute to long-COVID-associated cardiac dysfunction. Using thrombotic vascular tissues from patients with long COVID and induced pluripotent stem cell-derived ECs (iPSC-ECs), we modeled endotheliitis and observed similar dysfunction and cytokine upregulation, notably CCL2. Cardiac organoids comprising iPSC-ECs and iPSC-derived cardiomyocytes showed cardiac dysfunction after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, driven by CCL2. Profiling of chromatin accessibility and gene expression at a single-cell resolution linked CCL2 to ‘phenotype switching’ and cardiac dysfunction, validated by high-throughput proteomics. Disease modeling of cardiac organoids and exposure of human ACE2 transgenic mice to SARS-CoV-2 spike proteins revealed that CCL2-induced oxidative stress promoted post-translational modification of cardiac proteins, leading to cardiac dysfunction. These findings suggest that EC-released cytokines contribute to cardiac dysfunction in long COVID, highlighting the importance of early vascular health monitoring in patients with long COVID. Thomas, Noishiki, Gaddam et al. used thrombotic vascular tissues and iPSC-derived cardiac organoids to show that COVID-19-induced endotheliitis and cytokine release disrupt endothelial–cardiomyocyte crosstalk and contribute to cardiac dysfunction in long COVID.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 10","pages":"1249-1265"},"PeriodicalIF":9.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435943","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}

引用次数: 0

Endothelial cells as paracrine mediators of long COVID 内皮细胞是长 COVID 的旁分泌介质

IF 9.4

Nature cardiovascular research Pub Date : 2024-10-14 DOI: 10.1038/s44161-024-00551-8

Simon R. Foster, James E. Hudson

引用次数: 0