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

Joshua G. Travers, Fadia A. Kamal, Iñigo Valiente-Alandi, Michelle L. Nieman, Michelle A. Sargent, John N. Lorenz, Jeffery D. Molkentin, Burns C. Blaxall

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)958-971
Number of pages14
JournalJournal of the American College of Cardiology
Volume70
Issue number8
DOIs
StatePublished - Aug 22 2017

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Phosphotransferases
Ischemia
Heart Failure
Pharmacology
Myofibroblasts
Fibroblasts
Fibrosis
Wounds and Injuries
Cardiac Myocytes
Protein Subunits
GTP-Binding Proteins
Muscle Cells
Extracellular Matrix
Homeostasis
Therapeutics

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Travers, Joshua G. ; Kamal, Fadia A. ; Valiente-Alandi, Iñigo ; Nieman, Michelle L. ; Sargent, Michelle A. ; Lorenz, John N. ; Molkentin, Jeffery D. ; Blaxall, Burns C. / Pharmacological and Activated Fibroblast Targeting of Gβγ-GRK2 After Myocardial Ischemia Attenuates Heart Failure Progression. In: Journal of the American College of Cardiology. 2017 ; Vol. 70, No. 8. pp. 958-971.
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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.",
author = "Travers, {Joshua G.} and Kamal, {Fadia A.} and I{\~n}igo Valiente-Alandi and Nieman, {Michelle L.} and Sargent, {Michelle A.} and Lorenz, {John N.} and Molkentin, {Jeffery D.} and Blaxall, {Burns C.}",
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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 journalArticle

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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