Myocardial growth is a response of the cardiac muscle to altered conditions of hemodynamic load caused by a large number of physiological and pathophysiological conditions. Hypertrophic growth is triggered by an intricate web of interconnected signaling pathways and involves control at multiple molecular levels. Differences in the activation/inactivation of signaling mechanisms are generally believed to explain the differences in phenotype and prognosis among various forms of hypertrophy. While initially a functional (although not essential) compensation, persistent hypertrophy in response to excess hemodynamic workload often leads to ventricular remodeling with functional decompensation and development of overt heart failure. Enhanced signal transduction from cell-surface receptors to intracellular effectors via heterotrimeric Gq/11 proteins is well recognized to be centrally involved in hypertrophy development. Gq/11 signaling is integrated by Regulators of G protein Signaling (RGS) that are negative regulators of transmembrane signal duration and hormone sensitivity. Preliminary data have led to the following central hypotheses: (1) RGS2 is an important negative regulator of cardiac Gq/11 signaling and hypertrophy. (2) Down-regulation of RGS2 is critically involved in hypertrophy development by further enhancing Gq/11 signaling. (3) Enhanced Gq/11 signaling and its deleterious effects can be mitigated by increasing the amount/function of RGS2. (4) In light of recent evidence suggesting that RGS2 is a down-stream target for protein kinase G, we further hypothesize that cardiac RGS2 mediates cGMP-induced anti-hypertrophic effects. These hypotheses will be tested using gain- and loss-of-function approaches in the following Specific Aims: (1) To delineate the functional role of endogenous RGS2 in regulating Gq/11-mediated signaling and hypertrophy in isolated ventricular cardiomyocytes and the intact heart in vivo. (2) To determine whether conditional, cardiac-specific expression of RGS2 can attenuate Gq/11-mediated hypertrophy while preserving the heart's ability to adapt to an increase in demand. (3) To determine whether PKG-induced phosphorylation of RGS2 enhances its inhibitory effect on Gq/11 signaling and thereby provides crosstalk between cGMP and Gq/11 signaling. It is increasingly recognized that modulating negative regulators of hypertrophy could become an important strategy for heart failure treatment, because it attempts to mimic negative feedback mechanisms that are often central for maintaining cellular homeostasis Defining the biological role of RGS2 for cardiac signaling and function, combined with insights into how its regulatory properties could be exploited to modulate cardiac hypertrophic responses, may form the basis for therapeutic interventions aimed at fine-tuning Gq/11 signaling (i.e., preserving desirable features while targeting those that are maladaptive) through adjusting the activity and/or amount of RGS2.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080127-04
Application #
7619985
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Liang, Isabella Y
Project Start
2006-05-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
4
Fiscal Year
2009
Total Cost
$364,125
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
Zhang, Peng; Mende, Ulrike (2014) Functional role, mechanisms of regulation, and therapeutic potential of regulator of G protein signaling 2 in the heart. Trends Cardiovasc Med 24:85-93
Park-Windhol, Cindy; Zhang, Peng; Zhu, Ming et al. (2012) Gq/11-mediated signaling and hypertrophy in mice with cardiac-specific transgenic expression of regulator of G-protein signaling 2. PLoS One 7:e40048
Zhang, P; Su, J; Mende, U (2012) Cross talk between cardiac myocytes and fibroblasts: from multiscale investigative approaches to mechanisms and functional consequences. Am J Physiol Heart Circ Physiol 303:H1385-96
Desroches, B R; Zhang, P; Choi, B-R et al. (2012) Functional scaffold-free 3-D cardiac microtissues: a novel model for the investigation of heart cells. Am J Physiol Heart Circ Physiol 302:H2031-42
Chakir, Khalid; Zhu, Weizhong; Tsang, Sharon et al. (2011) RGS2 is a primary terminator of ??-adrenergic receptor-mediated G(i) signaling. J Mol Cell Cardiol 50:1000-7
Zhang, Peng; Su, Jialin; King, Michelle E et al. (2011) Regulator of G protein signaling 2 is a functionally important negative regulator of angiotensin II-induced cardiac fibroblast responses. Am J Physiol Heart Circ Physiol 301:H147-56
Pinz, Ilka; Zhu, Ming; Mende, Ulrike et al. (2011) An improved isolation procedure for adult mouse cardiomyocytes. Cell Biochem Biophys 61:93-101
Zhang, Peng; Mende, Ulrike (2011) Regulators of G-protein signaling in the heart and their potential as therapeutic targets. Circ Res 109:320-33