Pharmacological and activated fibroblast targeting of Gβγ-GRK2 after myocardial ischemia attenuates heart failure progression
Journal of the American College of Cardiology, 2017•jacc.org
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 βγ (Gβγ) subunits and their
interaction with G protein− coupled receptor kinase 2 (GRK2). Objectives: This study …
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 βγ (Gβγ) subunits and their
interaction with G protein− coupled receptor kinase 2 (GRK2). Objectives: This study …
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 βγ (Gβγ) subunits and their interaction with G protein−coupled receptor kinase 2 (GRK2).
Objectives
This study investigated the hypothesis that Gβγ-GRK2 inhibition and/or ablation after myocardial injury would attenuate pathological myofibroblast activation and cardiac remodeling.
Methods
The therapeutic potential of small molecule Gβγ-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 Gβγ-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 Gβγ-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 Gβγ-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, Gβγ-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 Gβγ-GRK2 inhibition in treating HF and the potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathological myofibroblast activation, interstitial fibrosis, and HF progression.
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