Abstract
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.
Highlights
Pathological remodeling of the heart is a hallmark of chronic heart failure (HF) and these structural changes further perpetuate the disease
To investigate if G protein-coupled receptor kinase 5 (GRK5) is required for fibroblast activation, we first isolated primary mice and adult cardiac fibroblasts (MACFs) from wild type (WT) and global GRK5KO mice for in vitro analysis (SI Appendix, Fig. S1) [27]
Fibroblasts make up a significant proportion of the heart with 11% of the heart composed of fibroblasts compared to 30% for cardiomyocytes [37]
Summary
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. AngII-AT1R signaling promotes fibroblast transdifferentiation through activation of calcium (Ca2+) signaling and subsequent gene transcription, primarily through the nuclear factor of activated T cells (NFAT) as well as release of TGFβ and subsequent autocrine TGFβ signaling [7, 10, 11]. GRK5 translocation to the nucleus has been shown to be crucial for pathological gene transcription following hypertrophic stress and this occurs via noncanonical actions [15,16,17,18] This occurs in myocytes downstream of Gαq activation that can occur through selective hypertrophic stressors, including α1-adrenergic and AngII-mediated signaling pathways [16]. Our incomplete understanding of these regulatory pathways that promote fibroblast activation has prevented the discovery of novel therapies to target the fibrotic response, which could affect many HF conditions, including HF with preserved ejection fraction
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