Heart failure (HF) is a progressive disease, affecting over 5 million individuals in the US alone, that is mediated in large part by increased neurohormone action at G protein-coupled receptors (GPCR). Inhibition of GPCR signaling with classical antagonists such as p-blockers can improve survival, but with varying degrees of success in different patient populations, thus alternative HF therapeutic strategies are needed. Arginine vasopressin (AVP) is a neurohormone that acts in the vasculature to modulate blood pressure and in the kidney to regulate water retention, but has also been shown to exert cardiac effects via the AVP type 1A receptor (VI AR). As with other neurohormones, AVP levels are elevated in patients with HF, which is associated with increased morbidity and mortality, and we have discovered that cardiac-specific V1 AR overexpression produces profound hypertrophy, fibrosis and failure, a process mediated through GOq protein-dependent signaling in the mouse heart. Conversely, we found that VI AR signaling though GPCR kinase (GRK)-dependent activation of extracellular-regulated kinase (ERK1/2) exerts survival effects. Thus, we hypothesize that although GOq protein-dependent V1 AR signaling can induce maladaptive hypertrophy and apoptosis, GRK-dependent VI AR signaling relays cardioprotective effects, the study of which will be the focus of Aim 1. Of clinical importance, many HF patients that are hospitalized due to acute exacerbation of their disease have their p-blocker therapy discontinued or reduced while at the same time may receive an AVP receptor antagonist to reduce hyponatremia secondary to high levels of AVP, which in some cases has been associated with increased mortality. There is currently no basic science or clinical data to guide physicians regarding these seemingly independent therapeutic interventions in terms of potential crosstalk. Our initial assessment of possible interactions between these GPCR systems showed that while AVP signaling significantly decreases the physiologic response to PAR agonists in isolated cardiomyocytes and in Langendorff-perfused hearts, VI AR stimulation results in enhanced recruitment of activated ERK1/2 to pi AR, which could promote protective signaling. Thus, we hypothesize that VI AR regulation of PAR signaling modulates cardiac function and survival, which will be the focus of Aim 2. The impact of VI ARdependent modulation of GRK- and pAR-dependent signaling on cardiac function and survival following cardiac injury will be the focus of Aim 3. Completion of these aims will enable us to establish a more rational approach to the development of novel HF strategies via selective or biased regulation of VI AR signaling.

Public Health Relevance

Heart failure (HF) is a highly prevalent disease, affecting millions of Americans. We have shown that cardiac AVP signaling impacts HF progression via different pathways. Understanding the mechanisms by which VI AR signaling mediates pro-survival signaling via modulation of GRK- and pAR-dependent pathways in the heart will allow the development of biased therapeutic strategies to simultaneously promote cardio-protection and block maladaptive renal and cardiac AVP effects to better treat HF patients with elevated levels of AVP.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL091799-06A1
Application #
8717104
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-05-05
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
$445,445
Indirect Cost
$159,445
Name
Temple University
Department
Type
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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-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
Carr 3rd, Richard; Schilling, Justin; Song, Jianliang et al. (2016) β-arrestin-biased signaling through the β2-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 β2-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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