Pharmacological and Activated Fibroblast Targeting of Gβγ-GRK2 After Myocardial Ischemia Attenuates Heart Failure Progression

BACKGROUND Cardiac fibroblasts are a critical cell population responsible for myocardial extracellular matrix homeostasis. Upon injury or pathological stimulation, these cells transform to an activated myofibroblast state and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation, a hallmark of heart failure (HF), induces pathological signaling through G protein beta gamma (G beta gamma) subunits and their interaction with G protein-coupled receptor kinase 2 (GRK2). OBJECTIVES This study investigated the hypothesis that G beta gamma-GRK2 inhibition and/or ablation after myocardial injury would attenuate pathological myofibroblast activation and cardiac remodeling. METHODS The therapeutic potential of small molecule G beta gamma-GRK2 inhibition, alone or in combination with activated fibroblast-or myocyte-specific GRK2 ablation-each initiated after myocardial ischemia-reperfusion (I/R) injury-was investigated to evaluate the possible salutary effects on post-I/R fibroblast activation, pathological remodeling, and cardiac dysfunction. RESULTS Small molecule G beta gamma-GRK2 inhibition initiated 1 week post-injury was cardioprotective in the I/R model of chronic HF, including preservation of cardiac contractility and a reduction in cardiac fibrotic remodeling. Systemic small molecule G beta gamma-GRK2 inhibition initiated 1 week post-I/R in cardiomyocyte-restricted GRK2 ablated mice (also post-I/R) still demonstrated significant cardioprotection, which suggested a potential protective role beyond the cardiomyocyte. Inducible ablation of GRK2 in activated fibroblasts (i.e., myofibroblasts) post-I/R injury demonstrated significant functional cardioprotection with reduced myofibroblast transformation and fibrosis. Systemic small molecule G beta gamma-GRK2 inhibition initiated 1 week post-I/R provided little to no further protection in mice with ablation of GRK2 in activated fibroblasts alone. Finally, G beta gamma-GRK2 inhibition significantly attenuated activation characteristics of failing human cardiac fibroblasts isolated from end-stage HF patients. CONCLUSIONS These findings suggested consideration of a paradigm shift in the understanding of the therapeutic role of G beta gamma-GRK2 inhibition in treating HF and the potential therapeutic role for G beta gamma-GRK2 inhibition in limiting pathological myofibroblast activation, interstitial fibrosis, and HF progression. (C) 2017 by the American College of Cardiology Foundation.