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DOI	10.1073/pnas.2012854118
	GRK5 is a regulator of fibroblast activation and cardiac fibrosis
	Eguchi A.; Coleman R.; Gresham K.; Gao E.; Ibetti J.; Chuprun J.K.; Koch W.J.
发表日期	2021
ISSN	00278424
卷号	118 期号:5
英文摘要	Pathological remodeling of the heart is a hallmark of chronic heart failure (HF) and these structural changes further perpetuate the disease. Cardiac fibroblasts are the critical cell type that is responsible for maintaining the structural integrity of the heart. Stress conditions, such as a myocardial infarction (MI), can activate quiescent fibroblasts into synthetic and contractile myofibroblasts. G protein-coupled receptor kinase 5 (GRK5) is an important mediator of cardiovascular homeostasis through dampening of GPCR signaling, and is expressed in the heart and up-regulated in human HF. Of note, GRK5 has been demonstrated to translocate to the nucleus in cardiomyocytes in a calcium-calmodulin (Ca2+-CAM)dependent manner, promoting hypertrophic gene transcription through activation of nuclear factor of activated T cells (NFAT). Interestingly, NFAT is also involved in fibroblast activation. GRK5 is highly expressed and active in cardiac fibroblasts; however, its pathophysiological role in these crucial cardiac cells is unknown. We demonstrate using adult cardiac fibroblasts that genetic deletion of GRK5 inhibits angiotensin II (AngII)-mediated fibroblast activation. Fibroblast-specific deletion of GRK5 in mice led to decreased fibrosis and cardiac hypertrophy after chronic AngII infusion or after ischemic injury compared to nontransgenic littermate controls (NLCs). Mechanistically, we show that nuclear translocation of GRK5 is involved in fibroblast activation. These data demonstrate that GRK5 is a regulator of fibroblast activation in vitro and cardiac fibrosis in vivo. This adds to previously published data which demonstrate the potential beneficial effects of GRK5 inhibition in the context of cardiac disease. © 2020 Proceedings of the National Academy of Sciences of the United States of America. All rights reserved.
英文关键词	Fibrosis; GRK5; Heart failure
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180810
作者单位	Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, United States; Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, United States
推荐引用方式 GB/T 7714	Eguchi A.,Coleman R.,Gresham K.,et al. GRK5 is a regulator of fibroblast activation and cardiac fibrosis[J],2021,118(5).
APA	Eguchi A..,Coleman R..,Gresham K..,Gao E..,Ibetti J..,...&Koch W.J..(2021).GRK5 is a regulator of fibroblast activation and cardiac fibrosis.Proceedings of the National Academy of Sciences of the United States of America,118(5).
MLA	Eguchi A.,et al."GRK5 is a regulator of fibroblast activation and cardiac fibrosis".Proceedings of the National Academy of Sciences of the United States of America 118.5(2021).