Exploring the Role and Therapeutic Potential of Gbeta/gamma-GRK2 Inhibition in Cardiac Fibroblasts, Fibrosis and Remodeling

Exploring the Role and Therapeutic Potential of Gbeta/gamma-GRK2 Inhibition in Cardiac Fibroblasts, Fibrosis and Remodeling

Bibliographic Details
Main Author: Travers, Joshua G.
Language:English
Published: University of Cincinnati / OhioLINK 2017
Subjects:
Pharmacology
Heart Failure
Cardiac Fibroblast
Fibrosis
Remodeling
Cardioprotection
Therapeutic
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511800749979715
id ndltd-OhioLink-oai-etd.ohiolink.edu-ucin1511800749979715
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Pharmacology
Heart Failure
Cardiac Fibroblast
Fibrosis
Remodeling
Cardioprotection
Therapeutic
spellingShingle Pharmacology
Heart Failure
Cardiac Fibroblast
Fibrosis
Remodeling
Cardioprotection
Therapeutic
Travers, Joshua G.
Exploring the Role and Therapeutic Potential of Gbeta/gamma-GRK2 Inhibition in Cardiac Fibroblasts, Fibrosis and Remodeling
author Travers, Joshua G.
author_facet Travers, Joshua G.
author_sort Travers, Joshua G.
title Exploring the Role and Therapeutic Potential of Gbeta/gamma-GRK2 Inhibition in Cardiac Fibroblasts, Fibrosis and Remodeling
title_short Exploring the Role and Therapeutic Potential of Gbeta/gamma-GRK2 Inhibition in Cardiac Fibroblasts, Fibrosis and Remodeling
title_full Exploring the Role and Therapeutic Potential of Gbeta/gamma-GRK2 Inhibition in Cardiac Fibroblasts, Fibrosis and Remodeling
title_fullStr Exploring the Role and Therapeutic Potential of Gbeta/gamma-GRK2 Inhibition in Cardiac Fibroblasts, Fibrosis and Remodeling
title_full_unstemmed Exploring the Role and Therapeutic Potential of Gbeta/gamma-GRK2 Inhibition in Cardiac Fibroblasts, Fibrosis and Remodeling
title_sort exploring the role and therapeutic potential of gbeta/gamma-grk2 inhibition in cardiac fibroblasts, fibrosis and remodeling
publisher University of Cincinnati / OhioLINK
publishDate 2017
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511800749979715
work_keys_str_mv AT traversjoshuag exploringtheroleandtherapeuticpotentialofgbetagammagrk2inhibitionincardiacfibroblastsfibrosisandremodeling
_version_ 1719453212059107328
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin15118007499797152021-08-03T07:04:45Z Exploring the Role and Therapeutic Potential of Gbeta/gamma-GRK2 Inhibition in Cardiac Fibroblasts, Fibrosis and Remodeling Travers, Joshua G. Pharmacology Heart Failure Cardiac Fibroblast Fibrosis Remodeling Cardioprotection Therapeutic Heart failure, the final clinical manifestation of numerous cardiovascular maladies, is a devastating disease characterized by interstitial fibrosis, chamber remodeling and reduced ventricular compliance. Elevated myocardial sympathetic stimulation, a hallmark of heart failure, induces pathological signaling through G protein βγ subunits that results in the activation and membrane recruitment of G protein-coupled receptor kinase 2 (GRK2). In the failing heart, diminished cardiac output triggers a vicious cycle of persistent sympathetic stimulation accompanied by perpetual maladaptive signaling due in large part to GRK2-mediated β-adrenergic receptor desensitization and loss of responsiveness. We recently identified and validated the novel small molecule inhibitor gallein that disrupts the Gβγ-GRK2 interaction.Here, we investigated the therapeutic potential of gallein in murine ischemia-reperfusion (I/R) injury, a clinically relevant model of ischemic heart failure. We found that pharmacological disruption of Gβγ-GRK2 signaling post-I/R offered significant protection against cardiac dysfunction and remodeling. Moreover, we observed that gallein treatment significantly ameliorated fibrotic infarct expansion and the expression of several pro-fibrotic markers, which likely contributed to the overall improvement in ventricular contractility.One principal objective was to decipher the cellular specificity of gallein by ablating GRK2 in various resident cell populations of the heart. While the salutary properties of cardiomyocyte-specific ablation of GRK2 have been extensively documented, our goal was to explore the potential cardiomyocyte-independent cardioprotective properties of gallein. While GRK2 ablation in cardiomyocytes offered modest protection against cardiac dysfunction and remodeling, it was only with concurrent gallein treatment that significant cardioprotection was achieved. These findings suggested functional significance for Gβγ-GRK2 inhibition in cell types beyond the cardiomyocyte.Cardiac fibroblasts are an essential cell population responsible for myocardial extracellular matrix homeostasis, however upon injury or pathological stimulation, these cells transform into activated myofibroblasts and play a fundamental role in myocardial fibrosis and remodeling. In this dissertation, we present evidence that gallein treatment reduces prototypical activation characteristics of cultured mouse cardiac fibroblasts, as well as human cardiac myofibroblasts isolated from patients with end-stage heart failure. We also demonstrate that pharmacological inhibition of Gβγ-GRK2 restores physiologic adrenergic receptor signaling in activated murine and human cardiac myofibroblasts.These discoveries warranted our exploration of the therapeutic potential of inducible ablation of GRK2 in activated cardiac fibroblasts after ischemic cardiac injury. Remarkably, mice with myofibroblast-specific deletion of GRK2 exhibited nearly complete preservation of cardiac function and significantly reduced fibrotic scar expansion post-I/R. As an unexpected consequence, concurrent gallein administration offered little to no further improvements to cardiac function or remodeling. These findings suggested the cardioprotective properties of gallein were significantly mediated through its effects in the activated cardiac myofibroblast.The results presented herein reveal the cardioprotective properties of pharmacological and activated fibroblast-specific targeting of the Gβγ-GRK2 interface in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression after ischemic myocardial insult. This work contributes further evidence to the beneficial effects of Gβγ-GRK2 inhibition, and offers significant potential to culminate in the development of direly needed novel therapeutic strategies for the treatment of heart failure. 2017 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511800749979715 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511800749979715 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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