Abstract 14173: Pharmacologic and Activated Fibroblast-Specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury
Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are largely responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transition to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately results in pathologic G protein-coupled receptor kinase 2 (GRK2)-mediated β-adrenergic receptor downregulation. We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast differentiation, interstitial fibrosis and the overall progression of heart failure.
To investigate this hypothesis, mice were subjected to ischemia/reperfusion injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein for 4 weeks. Animals receiving vehicle demonstrated severe cardiac dilatation and deterioration in overall cardiac function as measured by percent fractional shortening and ejection fraction. Remarkably, mice treated with gallein exhibited nearly complete preservation of cardiac function, along with reduced scar formation and fibrotic marker expression, suggesting a direct effect within the cardiac fibroblasts. To further explore possible mechanisms, activated fibroblast-restricted GRK2 knockout mice (GRK2fl x PeriostinMCM) were subjected to 4 weeks of ischemia/reperfusion injury. These animals displayed preserved myocardial function and reduced eccentric hypertrophy and collagen deposition compared to GRK2fl littermate controls. Finally, systemic Gβγ-GRK2 inhibition by gallein may not confer further protection over activated fibroblast-specific GRK2 ablation alone.
In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression. We believe this fibroblast-targeted approach will lead to the refinement of existing targets and compounds, and possibly the generation of novel therapeutics for the treatment of heart failure.
Author Disclosures: J.G. Travers: None. F.A. Kamal: None. M.L. Nieman: None. B.C. Blaxall: None.
- © 2015 by American Heart Association, Inc.