Targeting GRK2 (?ARK1) in Heart Failure ABSTRACT Heart Failure (HF) continues to grow in the country and is a burden to the health care enterprise. HF often occurs after myocardial injury or stress such as ischemia or pressure-overload with cardiac hypertrophy occurring first, followed by ventricular remodeling and a loss of contractile function and ?-adrenergic receptor (?AR) -mediated inotropic reserve. The G protein-coupled receptor (GPCR) kinase 2 (GRK2 or ?ARK1) plays a key role in the dysregulation of ?AR signaling in the hypertrophied and failing heart. Studies in transgenic mice using a peptide inhibitor of GRK2 (known as the ?ARKct) and also cardiac-specific GRK2 knockout (KO) mice suggest that GRK2 is a target to improve contractile function and ?AR-mediated inotropic reserve in HF. Of interest to this competitive renewal application, new data with ?ARKct expression in hearts and emerging data from GRK2 KO mice suggest that there are consequences of GRK2 inhibition or gene silencing that go beyond ?AR-mediated contractile function. For example, cardiac GRK2 KO mice have significantly limited myocyte hypertrophy in response to left ventricular (LV) pressure-overload, a phenotype also seen in ?ARKct mice with higher transgene expression. This occurs without the mice going into HF suggesting that GRK2 and its activity facilitate maladaptive cardiac hypertrophy. These data support the increasing evidence that a large and dynamic """"""""GRK2 interactome"""""""" exists in cells and extends GRK2 activity and regulation to proteins outside of GPCRs. Molecules shown to interact with GRK2 such as tubulin and Akt suggest that this GRK may play roles in adaptive myocyte shape and size as well as cell survival. In addition, GRK2 can be found in/on mitochondria in cardiac myocytes through novel protein-protein interaction via the amino-terminus of GRK2. Moreover, interesting data from non-myocytes have shown that GRK2 negatively affects insulin signaling and glucose metabolism. Specifically, GRK2 has been shown to inhibit the translocation of the glucose transporter, GLUT4, to cell membranes with consequential insulin resistance. Thus, regulation of glucose uptake, which is critical as an energy substrate in the ischemic and failing heart, could be an important novel target of GRK2 action. In this competitive renewal application we are interested in elucidating critical ?AR-independent actions of GRK2 in the heart and knowing whether ?ARKct-mediated GRK2 inhibition or loss of GRK2 expression promotes novel beneficial pathways in the stressed and compromised cardiomyocyte. The Central Hypothesis of this proposal is that GRK2 plays a critical role in pathological cardiac hypertrophy, ventricular remodeling and HF via mechanisms beyond GPCR desensitization, and this is determined by novel interactions and localization within the cardiomyocyte. Testing of this hypothesis will also show that lowering GRK2 expression is a novel strategy to improve the function of the failing heart. Our associated Specific Aims are: [1] To determine whether novel, non-GPCR desensitizing functions of GRK2 play a facilitative role in the pathogenesis of maladaptive cardiac hypertrophy;[2] To investigate the in vivo role of GRK2 in dysfunctional myocardial glucose uptake of ischemic myocardium and to determine the cellular mechanisms in myocytes of how GRK2 regulates glucose metabolism and insulin signaling;[3] To determine whether viral- mediated gene transfer of an artificial micro-RNA that targets and silences GRK2 expression offers a novel therapeutic strategy for pathological hypertrophy and ischemic HF.

Public Health Relevance

(Relevance): Since expression levels and activity of GRK2 are elevated in failing myocardium including in human heart failure (HF), uncovering novel mechanistic aspects of this GRK using our unique animal models and molecular reagents will lead to a broader understanding of the pathogenesis of hypertrophic and ischemic cardiac dysfunction. Moreover, our translational studies described will prove that GRK2 is an innovative therapeutic target for HF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL061690-16
Application #
8471154
Study Section
Special Emphasis Panel (ZRG1-CVS-D (02))
Program Officer
Adhikari, Bishow B
Project Start
1998-09-30
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
16
Fiscal Year
2013
Total Cost
$425,382
Indirect Cost
$147,355
Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Hullmann, Jonathan; Traynham, Christopher J; Coleman, Ryan C et al. (2016) The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development. Pharmacol Res 110:52-64
Woodall, Meryl C; Woodall, Benjamin P; Gao, Erhe et al. (2016) Cardiac Fibroblast GRK2 Deletion Enhances Contractility and Remodeling Following Ischemia/Reperfusion Injury. Circ Res 119:1116-1127
Waldschmidt, Helen V; Homan, Kristoff T; Cruz-Rodríguez, 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
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
Cannavo, Alessandro; Liccardo, Daniela; Lymperopoulos, Anastasios et al. (2016) β Adrenergic Receptor Kinase C-Terminal Peptide Gene-Therapy Improves β2-Adrenergic Receptor-Dependent Neoangiogenesis after Hindlimb Ischemia. J Pharmacol Exp Ther 356:503-13
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
Rengo, Giuseppe; Pagano, Gennaro; Filardi, Pasquale Perrone et al. (2016) Prognostic Value of Lymphocyte G Protein-Coupled Receptor Kinase-2 Protein Levels in Patients With Heart Failure. Circ Res 118:1116-24
Schumacher, Sarah M; Gao, Erhe; Cohen, Maya et al. (2016) A peptide of the RGS domain of GRK2 binds and inhibits Gα(q) to suppress pathological cardiac hypertrophy and dysfunction. Sci Signal 9:ra30
Trappanese, Danielle M; Liu, Yuchuan; McCormick, Ryan C et al. (2015) Chronic β1-adrenergic blockade enhances myocardial β3-adrenergic coupling with nitric oxide-cGMP signaling in a canine model of chronic volume overload: new insight into mechanisms of cardiac benefit with selective β1-blocker therapy. Basic Res Cardiol 110:456

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