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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Franco, Antonietta; Zhang, Lihong; Matkovich, Scot J et al. (2018) G-protein receptor kinases 2, 5 and 6 redundantly modulate Smoothened-GATA transcriptional crosstalk in fetal mouse hearts. J Mol Cell Cardiol 121:60-68
Dorn 2nd, Gerald W (2016) Canon Fodder-A Case for Contrarian Science. Circ Res 119:584-6
Dorn 2nd, Gerald W (2016) Central Parkin: The evolving role of Parkin in the heart. Biochim Biophys Acta 1857:1307-1312
Dorn 2nd, Gerald W (2015) Cardiac regeneration - Alchemy, science, and a wee bit of magic? J Mol Cell Cardiol 81:10-1
Shirihai, Orian S; Song, Moshi; Dorn 2nd, Gerald W (2015) How mitochondrial dynamism orchestrates mitophagy. Circ Res 116:1835-49
Westenbrink, B Daan; Ling, Haiyun; Divakaruni, Ajit S et al. (2015) Mitochondrial reprogramming induced by CaMKII? mediates hypertrophy decompensation. Circ Res 116:e28-39
Song, Moshi; Gong, Guohua; Burelle, Yan et al. (2015) Interdependence of Parkin-Mediated Mitophagy and Mitochondrial Fission in Adult Mouse Hearts. Circ Res 117:346-51
Song, Moshi; Matkovich, Scot J; Zhang, Yan et al. (2015) Combined cardiomyocyte PKC? and PKC? gene deletion uncovers their central role in restraining developmental and reactive heart growth. Sci Signal 8:ra39
Dorn 2nd, Gerald W (2013) Mitochondrial dynamism and cardiac fate--a personal perspective. Circ J 77:1370-9
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

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