Pathological cardiac hypertrophy is signaled largely through neurohormone receptor pathways transduced by the Gq heterotrimeric G-protein. The major terminal effectors of Gq signaling include Protein Kinase Cs (PKCs), and the major proximal signaling modulators include G-protein coupled Receptor Kinases (GRKs). Previously, we established that activation of GRKs and PKCs alters cardiomyocyte gene expression, cardiac contractility and ventricular remodeling in response to hemodynamic stress. We also have described clinical consequences of a functional GRK5 polymorphism in human heart failure. However, co-expression of multiple PKC and GRK kinase isoforms with overlapping and partially redundant functions in the heart has prevented clear delineation of isoform-specific GRK and PKC effects in heart disease. Doing so is important and timely for the following reasons: 1. Functional human GRK and PKC polymorphisms represent isoform-specific genetic perturbations whose consequences in health and disease need to be fully understood;2. Clinical and pre-clinical trials are already underway evaluating isoform-specific GRK2 and PKC? inhibition in cardiac ischemia and heart failure;and 3. A recent paradigm shift has revealed that GRKs not only terminate G- protein/PKC signaling, but concomitantly activate alternate G-protein-independent signaling through b- arrestins. For these reasons, we have developed novel floxed GRK and PKC isoform mice and used them to create unique cardiac-specific compound knockout models in which the individual effects of cardiac-expressed GRK2, GRK5, and GRK6, or of cardiac PKC? and PKC?, can be fully evaluated in the in vivo hypertrophying and failing heart. Our studies will critically examine the broad hypothesis that isoform-specific differential activation of G-protein-dependent PKC signaling and G-protein-independent GRK signaling pathways is a major determinant of the molecular, biochemical, and functional cardiac response to pressure overload. Using assays of gene expression, biochemical signal activity, protein expression, isolated cardiomyocyte function, and integrated cardiovascular function, we will systematically and comprehensively delineate isoform-specific GRK and PKC effects in developing, stable, and decompensating pathological (pressure overload) hypertrophy. The results of these functional genomics studies will move us closer to our long-term goal of more fully understanding the impact of neurohormonal/G-protein signaling on the heart, and of optimally directing existing and future therapeutics that interrupt such signaling in heart disease

Public Health Relevance

The reactive growth of cardiac muscle, termed cardiac hypertrophy, is a life-threatening condition common among patients with hypertension or after myocardial infarction. Some aspects of cardiac hypertrophy appear beneficial, like increased heart muscle that provides for greater pumping capacity. However, other aspects predispose to heart failure and sudden death, such as programmed cardiac myocyte death. Hypertrophy signaling is incredibly complex. Here, we will study unique genetic cardiac gene knockout mouse models that, for the first time, will help us identify and define specific drugable cardiac kinases that separately mediate beneficial and deleterious features of cardiac hypertrophy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Adhikari, Bishow B
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Fan, Qian; Chen, Mai; Zuo, Lin et al. (2013) Myocardial Ablation of G Protein-Coupled Receptor Kinase 2 (GRK2) Decreases Ischemia/Reperfusion Injury through an Anti-Intrinsic Apoptotic Pathway. PLoS One 8:e66234
Sorriento, D; Fusco, A; Ciccarelli, M et al. (2013) Mitochondrial G protein coupled receptor kinase 2 regulates proinflammatory responses in macrophages. FEBS Lett 587:3487-94
Dorn 2nd, Gerald W (2013) Mitochondrial dynamism and cardiac fate--a personal perspective. Circ J 77:1370-9
Rivas, Veronica; Carmona, Rita; Munoz-Chapuli, Ramon et al. (2013) Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2. J Clin Invest 123:4714-30
Ciccarelli, Michele; Sorriento, Daniela; Franco, Antonietta et al. (2013) Endothelial G protein-coupled receptor kinase 2 regulates vascular homeostasis through the control of free radical oxygen species. Arterioscler Thromb Vasc Biol 33:2415-24
Vasudevan, Neelakantan T; Mohan, Maradumane L; Gupta, Manveen K et al. (2013) G*ýý-independent recruitment of G-protein coupled receptor kinase 2 drives tumor necrosis factor *-induced cardiac *-adrenergic receptor dysfunction. Circulation 128:377-87
Raake, Philip W; Zhang, Xiaoying; Vinge, Leif E et al. (2012) Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction. Circulation 125:2108-18
Dorn 2nd, Gerald W (2012) Decoding the cardiac message: the 2011 Thomas W. Smith Memorial Lecture. Circ Res 110:755-63
Fusco, Anna; Santulli, Gaetano; Sorriento, Daniela et al. (2012) Mitochondrial localization unveils a novel role for GRK2 in organelle biogenesis. Cell Signal 24:468-75
Dorn 2nd, Gerald W (2011) The genomic architecture of sporadic heart failure. Circ Res 108:1270-83

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