Prodeath Signaling of G Protein-Coupled Receptor Kinase 2 in Cardiac Myocytes After Ischemic Stress Occurs via Extracellular Signal-Regulated Kinase-Dependent Heat Shock Protein 90-mediated Mitochondrial Targeting
Mai Chen,Priscila Y. Sato,J. Kurt Chuprun,Raymond J. Peroutka,Nicholas J. Otis,Jessica Ibetti,Shi Pan,Shey-Shing Sheu,Erhe Gao,Walter J. Koch +9 more
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TLDR
G protein–coupled receptor kinase 2 is identified as a prodeath kinase in the heart, acting in a novel manner through mitochondrial localization via extracellular signal–regulated kinase regulation.Abstract:
Rationale:G protein–coupled receptor kinase 2 (GRK2) is abundantly expressed in the heart, and its expression and activity are increased in injured or stressed myocardium. This upregulation has been shown to be pathological. GRK2 can promote cell death in ischemic myocytes, and its inhibition by a peptide comprising the last 194 amino acids of GRK2 (known as carboxyl-terminus of β-adrenergic receptor kinase [bARKct]) is cardioprotective. Objective:The aim of this study was to elucidate the signaling mechanism that accounts for the prodeath signaling seen in the presence of elevated GRK2 and the cardioprotection afforded by the carboxyl-terminus of β-adrenergic receptor kinase. Methods and Results:Using in vivo mouse models of ischemic injury and also cultured myocytes, we found that GRK2 localizes to mitochondria, providing novel insight into GRK2-dependent pathophysiological signaling mechanisms. Mitochondrial localization of GRK2 in cardiomyocytes was enhanced after ischemic and oxidative stress, events...read more
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Electrical and mechanical stimulation of cardiac cells and tissue constructs.
TL;DR: The biological underpinnings of both mechanical and electrical signaling, as identified via studies related to cardiac development and those related to an evaluation of cardiac disease progression are sought, as well as the development of bioreactors that combine electrical and mechanical stimulation in order to mimic the complex signaling environment present in vivo.
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Signaling Pathways in Cardiac Myocyte Apoptosis.
TL;DR: Recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways is summarized, with a focus on the involvement of these pathways in the pathogenesis of heart disease.
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The evolving impact of g protein-coupled receptor kinases in cardiac health and disease.
TL;DR: The current data on GRKs related to cardiac disease are reviewed and their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure is discussed.
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Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction
Sarah M. Schumacher,Erhe Gao,Weizhong Zhu,Xiongwen Chen,J. Kurt Chuprun,Arthur M. Feldman,John J.G. Tesmer,Walter J. Koch +7 more
TL;DR: It is reported that paroxetine can block or even reverse heart damage after myocardial infarction in a mouse model and represents a potential repurposing of this drug, as well as a starting point for innovative small-molecule GRK2 inhibitor development.
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Targeting cardiac β-adrenergic signaling via GRK2 inhibition for heart failure therapy
TL;DR: This review will explore recent research regarding GRK2 inhibition and focus on theGRK2 inhibitor peptide known as βARKct, which represents new hope in the treatment against HF progression.
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