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GRK5 IS A NOVEL REGULATOR OF FIBROBLAST ACTIVATION AND CARDIAC FIBROSIS

Rationale: 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 (GPCR) kinase (GRK) 5 is an important mediator of cardiovascular homeostasis through dampening of GPCR signaling, and is expressed in the heart and upregulated 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 NFAT. Interestingly, NFAT is also involved in fibroblast activation. GRK5 is highly expressed and active in cardiac fibroblasts (CFs), however its pathophysiological role in these crucial cardiac cells is unknown. Objective: The aim of this study is to elucidate the role of GRK5 in the activation of cardiac fibroblasts in vitro and cardiac fibrosis after injury in vivo. Methods and Results: 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 decreased fibrosis and cardiac hypertrophy after chronic AngII infusion compared to non-transgenic littermate controls (NLCs). Fibroblast-specific deletion of GRK5 was also protective in mice after ischemic injury as they presented with preserved systolic function, decreased fibrosis, and decreased hypertrophy compared to NLCs. Mechanistically, we show that nuclear translocation of GRK5 is involved in fibroblast activation. Conclusions: We present novel data demonstrating that GRK5 is a regulator of fibroblast activation in vitro and cardiac fibrosis in vivo. This adds to previously published data which demonstrates the potential beneficial effects of GRK5 inhibition in the context of cardiac disease. / Biomedical Sciences

Identiferoai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/536
Date January 2022
CreatorsEguchi, Akito
ContributorsKoch, Walter J., Cheung, Joseph, Drosatos, Konstantinos, Elrod, John W., Tilley, Douglas G., Grisanti, Laurel, A. (Laurel Ann), 1983-
PublisherTemple University. Libraries
Source SetsTemple University
LanguageEnglish
Detected LanguageEnglish
TypeThesis/Dissertation, Text
Format113 pages
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Relationhttp://dx.doi.org/10.34944/dspace/518, Theses and Dissertations

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