Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 958-971 |
| Number of pages | 14 |
| Journal | Journal of the American College of Cardiology |
| Volume | 70 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 22 2017 |
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All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine
Cite this
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Pharmacological and Activated Fibroblast Targeting of Gβγ-GRK2 After Myocardial Ischemia Attenuates Heart Failure Progression. / Travers, Joshua G.; Kamal, Fadia A.; Valiente-Alandi, Iñigo; Nieman, Michelle L.; Sargent, Michelle A.; Lorenz, John N.; Molkentin, Jeffery D.; Blaxall, Burns C.
In: Journal of the American College of Cardiology, Vol. 70, No. 8, 22.08.2017, p. 958-971.Research output: Contribution to journal › Article
TY - JOUR
T1 - Pharmacological and Activated Fibroblast Targeting of Gβγ-GRK2 After Myocardial Ischemia Attenuates Heart Failure Progression
AU - Travers, Joshua G.
AU - Kamal, Fadia A.
AU - Valiente-Alandi, Iñigo
AU - Nieman, Michelle L.
AU - Sargent, Michelle A.
AU - Lorenz, John N.
AU - Molkentin, Jeffery D.
AU - Blaxall, Burns C.
PY - 2017/8/22
Y1 - 2017/8/22
N2 - 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.
AB - 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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U2 - 10.1016/j.jacc.2017.06.049
DO - 10.1016/j.jacc.2017.06.049
M3 - Article
C2 - 28818206
AN - SCOPUS:85026799213
VL - 70
SP - 958
EP - 971
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 8
ER -