RGS proteins: identifying new GAPs in the understanding of blood pressure regulation and cardiovascular function

Abstract

Understanding the mechanisms that underlie BP (blood pressure) variation in humans and animal models may provide important clues for reducing the burden of uncontrolled hypertension in industrialized societies. High BP is often associated with increased signalling via G-protein-coupled receptors. Three members of the RGS (regulator of G-protein signalling) superfamily RGS2, RGS4 and RGS5 have been implicated in the attenuation of G-protein signalling pathways in vascular and cardiac myocytes, as well as cells of the kidney and autonomic nervous system. In the present review, we discuss the current state of knowledge regarding their differential expression and function in cardiovascular tissues, and the likelihood that one or more of these alleles are candidate hypertension genes. Together, findings from the studies described herein suggest that development of methods to modulate the expression and function of RGS proteins may be a possible strategy for the treatment and prevention of hypertension and cardiovascular disease.

Identification of a cAMP-response Element in the Regulator of G-protein Signaling-2 (RGS2) Promoter as a Key Cis-regulatory Element for RGS2 Transcriptional Regulation by Angiotensin II in Cultured Vascular Smooth Muscles

“…Moreover, we identified a conserved cAMP-response element (CRE) in the murine RGS2 promoter that is critical for cAMP-response element-binding protein (CREB) binding and RGS2 promoter activation. Forskolin-stimulated RGS2 mRNA up-regulation is inhibited by CREB sequestration or specific disruption of the CREB-RGS2 promoter interaction, and Ang IIinduced CREB phosphorylation and nuclear localization are blocked by iPLA 2 ␤ pharmacologic inhibition or genetic ablation. Ang II-induced intracellular cyclic AMP accumulation precedes CREB phosphorylation and is diminished by inhibiting iPLA 2 , cyclooxygenase, or lipoxygenase.…”

“…RGS2 is expressed ubiquitously, and its major biological function is to serve as a GTPase-activating protein that preferentially attenuates heterotrimeric G protein G␣ q/11 GTPase activity (2). Several independent studies have demonstrated that Rgs2 knock-out mice have severe hypertension (3)(4)(5)(6)(7), suggesting that RGS2 plays a critical role in blood pressure homeostasis.…”

“…Chem. 282, 25278 -25289), but the specific molecular causes and consequences of iPLA 2 ␤ activation are not known. Here we demonstrate that both protein kinases C (PKC) and A (PKA) participate in Ang II-induced VSMC RGS2 mRNA up-regulation, and that actions of PKC and PKA precede and follow iPLA 2 ␤ activation, respectively.…”

“…282, 25278 -25289), but the specific molecular causes and consequences of iPLA 2 ␤ activation are not known. Here we demonstrate that both protein kinases C (PKC) and A (PKA) participate in Ang II-induced VSMC RGS2 mRNA up-regulation, and that actions of PKC and PKA precede and follow iPLA 2 ␤ activation, respectively. Moreover, we identified a conserved cAMP-response element (CRE) in the murine RGS2 promoter that is critical for cAMP-response element-binding protein (CREB) binding and RGS2 promoter activation.…”

“…Ang II binds to VSMC AT1 receptors, which results in G protein G q/11 activation, smooth muscle contraction, and increased blood pressure (14). Ang II also initiates a negative feedback loop simultaneously to restrain its vasopressor effects (2), and elements of this loop include Ang II-induced increases in RGS2 expression. The importance of this feedback loop in blood pressure homeostasis is reflected by the fact that infusion of Ang II results in an exaggerated hypertensive response in Rgs2-null mice compared with their wild-type (WT) littermates (7).…”