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

Zhongwen Xie, Dexiang Liu, Shu Liu, Lindsay Calderon, Guogang Zhao, John Turk, Zhenheng Guo

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Mice deficient in regulator of G-protein signaling-2 (RGS2) have severe hypertension, and RGS2 genetic variations occur in hypertensive humans. A potentially important negative feedback loop in blood pressure homeostasis is that angiotensin II (Ang II) increases vascular smooth muscle cell (VSMC) RGS2 expression. We reported that Group VIA phospholipase A 2(iPLA 2β) is required for this response (Xie, Z., Gong, M. C., Su, W., Turk, J., and Guo, Z. (2007) J. Biol. Chem. 282, 25278-25289), but the specific molecular causes and consequences of iPLA 2β 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 2β 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. Forskolin-stimulated RGS2 mRNA up-regulation is inhibited by CREB sequestration or specific disruption of the CREB-RGS2 promoter interaction, and Ang II-induced CREB phosphorylation and nuclear localization are blocked by iPLA 2β pharmacologic inhibition or genetic ablation. Ang II-induced intracellular cyclic AMP accumulation precedes CREB phosphorylation and is diminished by inhibiting iPLA2, cyclooxygenase, or lipoxygenase. Moreover, three single nucleotide polymorphisms identified in hypertensive patients are located in the human RGS2 promoter CREB binding site. Point mutations corresponding to these single nucleotide polymorphisms interfere with stimulation of human RGS2 promoter activity by forskolin. Our studies thus delineate a negative feedback loop to attenuate Ang II signaling in VSMC with potential importance in blood pressure homeostasis and the pathogenesis of human essential hypertension.

Original languageEnglish
Pages (from-to)44646-44658
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number52
DOIs
StatePublished - Dec 30 2011

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