Deregulation of RGS2 in cardiovascular diseases

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 selectively 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.

Figure 1

Regulation of RGS2 in the cardiac myocyte and its implication in cardiac hypertrophy.1. Cardiac hypertrophic agonists stimulate G_alphaq/11-coupled GPCRs and activate phospholipase C-beta (PLC-beta). Subsequent production of IP₃ and elevation of intracellular Ca²⁺ levels not only activate Ca²⁺/calmodulin-dependent protein kinase II (CAMKII), calcineurin (CN) and regulator of CN-1 (RCAN-1), but also MAPK including ERK1/2 and JNK. Activated CN dephosphorylates NFAT, which promotes its nuclear translocation. The cooperation of NFAT and GATA then switches on transcription of the hypertrophic gene program. Of note, the hypertrophic responses were abolished in response to administration of PLC-beta inhibitor, U7122.2. RGS2 negatively regulates G_alphaq/11 signaling. Association of RGS2 with G_alphaq/11 increases the GTPase activity of G_alphaq/11 thus suppressing the G_alphaq/11-mediated hypertrophic responses. Our lab has recently shown that RGS2 also negatively regulates G_alphai/o. 3. The expression of RGS2 is biphasically regulated, with a marked up-regulation in response to short term G_alphaq/11 or G_alphaS activation followed by a persistent decline in response to sustained agonist stimulation. 4. The activity of RGS2 is regulated by PKG. PDE5 inhibition-mediated PKGI-activation translocates, phosphorylates and activates RGS2. Apart from PDE inhibition, PKG is also activated by ANP-mediated GC-A activation. Given that PKG phosphorylates both RGS2 and RGS4, RGS2 might be a potential downstream effector of the GC-A/PKG signaling.