[Frontiers in Bioscience S2, 547-557, January 1, 2010]

Deregulation of RGS2 in cardiovascular diseases

Sharon Tsang1, Anthony Yiu-Ho Woo1, Weizhong Zhu1, Rui-Ping Xiao1

1Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, MD 21224

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The Role of RGS2 in Cardiovascular Diseases
3.1. Deregulation of RGS2 in the vascular system and hypertension
3.1.1. Potential role of Galpha12/13
3.2. Deregulation of RGS2 and cardiac hypertrophy
3.2.1. Galphaq/11 signaling and cardiac hypertrophy
3.2.2. Role of RGS2 in cardiac hypertrophy
3.2.3. Potential mechanisms underlying RGS2-mediated suppression of hypertrophy
3.2.4. Potential overlapping roles of RGS proteins
3.3. Role of RGS2 in the development of heart failure
4. Regulation of RGS2 4.1 .G-protein dependent regulation of RGS2 expression
4.1.1. Galphaq/11-RGS2- Galphaq/11 negative feedback loop
4.1.2. GalphaS -RGS2- Galphaq/11Galphai/o signaling cross-talk?
4.1.3. Biphasic regulation of RGS2 expression
4.1.4. Deregulation of G-protein-dependent axis and its pathophysiological implications
4.2. PKG dependent regulation of RGS2 activity
4.2.1. G-protein-independent regulation of RGS2 by NO-cGMP-PKG signaling cascade in VSMC
4.2.2. G-protein-independent regulation of RGS2 by cGMP-PKG-PDE5 signaling axis in the heart
4.2.3. G-protein-dependent regulation of RGS2 by GC-A-cGMP-PKG axis in the myocardium?
4.2.4. Deregulation of the PKG axis - the implications
5. Perspective

1. ABSTRACT

Alteration of G protein-coupled receptor (GPCR) signaling is a salient feature of hypertension and the associated heart diseases. Recent studies have revealed a large family of Regulators of G-protein Signaling (RGS) proteins as important endogenous regulators of GPCR signaling. RGS2 selective regulates Galphaq/11 signaling, an essential cause of hypertension and cardiac hypertrophy. Both clinical and animal studies have shown that deregulation of RGS2 leads to exacerbated Galphaq/11 signaling. There is an inverse correlation between RGS2 expression and blood pressure, as well as a selective down-regulation of RGS2 in various models of cardiac hypertrophy. The causal relationship has been established in animal studies. RGS2 knockout mice exhibit not only hypertension phenotype but also accelerated cardiac hypertrophy and heart failure in response to pressure-overload. Further in vitro studies have shown that RGS2 knockdown with RNA interference exacerbates, whilst RGS2 over-expression completely abolishes the Galphaq/11-induced hypertrophy. These findings indicate that deregulation of RGS2 plays a crucial role in the pathogenesis of cardiovascular diseases, marking RGS2 as a potential therapeutic target or biomarker of hypertension or hypertensive heart diseases.