Abstract 262: GRK5 is a Novel Regulator of Fibroblast Activation
Eguchi, A; Koch, WJ
Published in: Circulation Research
Pathological remodeling of the heart is a hallmark of heart failure (HF) and these structural changes of the heart further perpetuates 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, can activate and induce the transdifferentiation of quiescent fibroblasts into synthetic and contractile myofibroblasts. G protein-coupled receptor (GPCR) kinases (GRKs) are important mediators of cardiovascular homeostasis through dampening of GPCR signaling. Recently, non-canonical activities of these GRKs have been elucidated. GRK5 is one isoform of these kinases that is expressed in the heart and has been shown to be up-regulated in human HF. Of note, GRK5 has been demonstrated to translocate to the nucleus in cardiomyocytes, promoting hypertrophic gene transcription through activation of nuclear factor of activated T-cells (NFAT) and nuclear factor κB (NFκB). Interestingly, these transcription factors are also involved in fibroblast activation and transdifferentiation. GRK5 is highly expressed and active in cardiac fibroblasts, however its physiological and pathological role in these crucial cardiac cells is unknown. Utilizing adult mouse cardiac fibroblasts
, our preliminary data suggests a relevant role for GRK5 in the activation and function of fibroblasts. We observed that genetic deletion of GRK5 in cardiac fibroblasts attenuated α smooth muscle actin (α-SMA) expression, a classical myofibroblast marker, after stimulation with Transforming Growth Factor β (TGFβ) and Angiotensin II (AngII). In addition, deletion of GRK5 diminished the expression of myofibroblast specific genes and proteins such as Collagen I and II after AngII stimulation and were refractory to TGFβ and AngII mediated collagen gel contraction. Conversely, GRK5 overexpression led to an increase in differentiation markers such as α-SMA. These data support the hypothesis that GRK5 is an essential regulator of fibroblast activation. GRK5 fibroblast knockout mice are currently being examined to determine if GRK5 regulates fibroblast transdifferentiation
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