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GRK5 is a regulator of fibroblast activation and cardiac fibrosis [Medical Sciences]
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2021-02-02 , DOI: 10.1073/pnas.2012854118
Akito Eguchi 1 , Ryan Coleman 1 , Kenneth Gresham 1 , Erhe Gao 1 , Jessica Ibetti 1 , J Kurt Chuprun 1 , Walter J Koch 2, 3
Affiliation  

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.



中文翻译:

GRK5 是成纤维细胞活化和心脏纤维化的调节剂 [医学]

心脏的病理性重塑是慢性心力衰竭 (HF) 的标志,这些结构变化进一步使该疾病长期存在。心脏成纤维细胞是负责维持心脏结构完整性的关键细胞类型。压力条件,例如心肌梗塞 (MI),可以将静止的成纤维细胞激活为合成和收缩的肌成纤维细胞。G 蛋白偶联受体激酶 5 (GRK5) 是通过抑制 GPCR 信号传导来调节心血管稳态的重要介质,在心脏中表达并在人 HF 中上调。值得注意的是,已证明 GRK5 在钙调蛋白(Ca 2+-CAM) 依赖性方式,通过激活活化 T 细胞核因子 (NFAT) 促进肥大基因转录。有趣的是,NFAT 也参与成纤维细胞的活化。GRK5 在心脏成纤维细胞中高度表达和活跃;然而,它在这些关键心脏细胞中的病理生理作用尚不清楚。我们使用成人心脏成纤维细胞证明 GRK5 的遗传缺失抑制血管紧张素 II (AngII) 介导的成纤维细胞活化。与非转基因同窝小鼠 (NLC) 相比,小鼠中 GRK5 的成纤维细胞特异性缺失导致慢性 AngII 输注或缺血性损伤后纤维化和心脏肥大减少。从机制上讲,我们表明 GRK5 的核转位与成纤维细胞活化有关。这些数据表明GRK5是体外成纤维细胞活化和体内心脏纤维化的调节剂。这增加了先前公布的数据,这些数据证明了 GRK5 抑制在心脏病背景下的潜在有益作用。

更新日期:2021-01-27
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