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J. Biol. Chem., Vol. 282, Issue 35, 25278-25289, August 31, 2007

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Group VIA Phospholipase A₂ (iPLA₂) Participates in Angiotensin II-induced Transcriptional Up-regulation of Regulator of G-protein Signaling-2 in Vascular Smooth Muscle Cells^*

Zhongwen Xie, Ming C. Gong, Wen Su, John Turk, and Zhenheng Guo¹

From the Department of Physiology and the Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536 and the Division of Endocrinology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Rgs2 (regulator of G-protein signaling-2)-deficient mice exhibit severe hypertension, and genetic variations of RGS2 occur in hypertensive patients. RGS2 mRNA up-regulation by angiotensin II (Ang II) in vascular smooth muscle cells (VSMC) is a potentially important negative feedback mechanism in blood pressure homeostasis, but how it occurs is unknown. Here we demonstrate that group VIA phospholipase A₂ (iPLA₂) plays a pivotal role in Ang II-induced RGS2 mRNA up-regulation in VSMC by three independent approaches, including pharmacologic inhibition with a bromoenol lactone suicide substrate, suppression of iPLA₂ expression with antisense oligonucleotides, and genetic deletion in iPLA₂-null mice. Selective inhibition of iPLA₂ by each of these approaches abolishes Ang II-induced RGS2 mRNA up-regulation. Furthermore, using adenovirus-mediated gene transfer, we demonstrate that restoration of iPLA₂-expression in iPLA₂-null VSMC reconstitutes the ability of Ang II to up-regulate RGS2 mRNA expression. In contrast, Ang II-induced vasodilator-stimulated phosphoprotein phosphorylation and Ang II receptor expression are unaffected. Moreover, in wild-type but not iPLA₂-null VSMC, Ang II stimulates iPLA₂ enzymatic activity significantly. Both arachidonic acid and lysophosphatidylcholine, products of iPLA₂ action, induce RGS2 mRNA up-regulation. Inhibition of lipoxygenases, particularly 15-lipoxygenase, and cyclooxygenases, but not cytochrome P450-dependent epoxygenases inhibits Ang II- or AA-induced RGS2 mRNA expression. Moreover, RGS2 protein expression is also up-regulated by Ang II, and this is attenuated by bromoenol lactone. Disruption of the Ang II/iPLA₂/RGS2 feedback pathway in iPLA₂-null cells potentiates Ang II-induced vasodilator-stimulated phosphoprotein and Akt phosphorylation in a time-dependent manner. Collectively, our results demonstrate that iPLA₂ participates in Ang II-induced transcriptional up-regulation of RGS2 in VSMC.

Received for publication, December 6, 2006 , and in revised form, July 5, 2007.

^* This work was supported by a Scientist Development Grant from the American Heart Association (to Z. G.), National Institutes of Health Grants HL67284 and HL082791, and Career Development Award 1-04-CD-04 from American Diabetes Association (to M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 569 Wethington Bldg., 900 South Limestone, Lexington, KY 40536. Tel.: 859-323-4933 (ext. 81416); Fax: 859-257-3646; E-mail: zguo2{at}uky.edu.

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