Heart failure (HF) continues to be a major health problem and is an end-point of cardiac injury, which in many cases is preceded by cardiac hypertrophy and adverse remodeling. We have found that G protein-coupled receptor (GPCR) signaling and regulation of this signaling by GPCR kinases (GRKs) play crucial roles in the pathological processes of maladaptive cardiac hypertrophy and ventricular remodeling. GRK2 and GRKS are the major cardiac GRKs and both have been found to be up-regulated in failing human myocardium so their function in the injured heart is of significance. In the first funding cycle of this Project, we have identified that GRKS plays a novel non-GRK role in cardiomyocyte signaling and function within the nucleus of myocytes acting as a Class II histone deacetylase (HDAC) kinase. This HDAC kinase activity of GRKS can facilitate maladaptive cardiac hypertrophy and accelerate HF development. We now have new preliminary data to suggest there are additional targets within the myocyte for GRKS, including in the nucleus, that can promote myocyte dysfunction. Included is the nuclear factor of activated T-cell (NFAT) pathway and it appears that GRKS can activate this critical molecule in the heart. We will also investigate the role of GRKS in ischemic injury and repair and have assembled several key mouse models and viral constructs to delineate specific pathological and therapeutic mechanisms surrounding this kinase. Included is the development of a novel knock-in mouse where all endogenous GRKS will be defective in its ability to enter the nucleus. Using these we will test the Central Hypothesis that GRKS plays a critical (patho)- physiological role in the cardiomyocyte's response to injury and targeting and manipulating its unique cellular localization and activity is a novel therapeutic strategy for preventing maladaptive cardiac hypertrophy, ventricular remodeling and HF. Our associated Specific Aims to test this hypothesis are:  To determine the mechanisms involved in the GRKS-mediated regulation of cardiac NFAT signaling; To determine the mechanistic role of nuclear GRKS activity in the heart's response to ischemic injury;and  To determine the ultimate physiological role for nuclear GRKS activity and localization in cardiac injury and repair.
Heart failure (HF) is a major health problem throughout the world and understanding molecular processes involved in cardiac injury and repair can advance development of novel therapies. We have found that a specific kinase, GRKS, can play a key role in HF pathogenesis and through continued GRKS-targeted research in this area can lead to translatable strategies to combat cardiac injury HF.
|Wasilewski, Melissa A; Myers, Valerie D; Recchia, Fabio A et al. (2016) Arginine vasopressin receptor signaling and functional outcomes in heart failure. Cell Signal 28:224-33|
|Feldman, Arthur M; Gordon, Jennifer; Wang, JuFang et al. (2016) BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes. J Mol Cell Cardiol 92:10-20|
|Waldschmidt, Helen V; Homan, Kristoff T; Cruz-RodrÃguez, Osvaldo et al. (2016) Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors. J Med Chem 59:3793-807|
|Carr 3rd, Richard; Schilling, Justin; Song, Jianliang et al. (2016) Î²-arrestin-biased signaling through the Î²2-adrenergic receptor promotes cardiomyocyte contraction. Proc Natl Acad Sci U S A 113:E4107-16|
|Grisanti, Laurel A; Gumpert, Anna M; Traynham, Christopher J et al. (2016) Leukocyte-Expressed Î²2-Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury. Circulation 134:153-67|
|Cannavo, Alessandro; Liccardo, Daniela; Eguchi, Akito et al. (2016) Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases. Nat Commun 7:10877|
|Zhou, Jibin; Ahmad, Firdos; Parikh, Shan et al. (2016) Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy. Circ Res 118:1208-22|
|Woodall, Benjamin P; Woodall, Meryl C; Luongo, Timothy S et al. (2016) Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy. J Biol Chem 291:21913-21924|
|Traynham, Christopher J; Hullmann, Jonathan; Koch, Walter J (2016) "Canonical and non-canonical actions of GRK5 in the heart". J Mol Cell Cardiol 92:196-202|
|Khan, Mohsin; Koch, Walter J (2016) c-kit+ Cardiac Stem Cells: Spontaneous Creation or a Perplexing Reality. Circ Res 118:783-5|
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