Key result
Pharmacological Gβγ-GRK2 inhibition with gallein or activated fibroblast-specific GRK2 ablation initiated 1 week after myocardial ischemia-reperfusion significantly preserved contractile performance and attenuated pathological fibrotic remodeling.
Why the study?
Chronic sympathetic overstimulation in heart failure induces pathological Gβγ-GRK2 signaling contributing to myofibroblast activation and myocardial fibrosis, but the therapeutic potential of targeting this pathway post-myocardial ischemia was unclear.
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“Regrettably, there are essentially no clinical interventions that effectively target these tissue-damaging cardiac fibroblasts. This work may provide evidence that shifts the way we think about treating heart failure. Not only has our study identified the cardio-protective properties of pharmacological and fibroblast-specific Gβγ-GRK2 inhibition in a clinically relevant mouse model, we also showed that inhibition reduced the activation of human heart failure cardiac fibroblasts. This is a key cell type responsible for the scarring of heart tissue.”
Pharmacological inhibition or activated fibroblast-specific ablation of Gβγ-GRK2 signaling post-myocardial injury significantly attenuates fibrotic remodeling and preserves cardiac function.
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 subunits and their interaction with G protein-coupled receptor kinase 2 (GRK2). OBJECTIVES We hypothesized 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 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 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, suggesting 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 our 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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Travers et al. (2017) studied Heart failure following myocardial ischemia-reperfusion injury. Gallein and activated fibroblast-specific GRK2 ablation vs. Vehicle or sham-operated controls was evaluated on Cardiac function (ejection fraction, fractional shortening) and pathological fibrotic remodeling (infarct expansion). Pharmacological Gβγ-GRK2 inhibition with gallein or activated fibroblast-specific GRK2 ablation initiated 1 week after myocardial ischemia-reperfusion significantly preserved contractile performance and attenuated pathological fibrotic remodeling.
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