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J. Biol. Chem., Vol. 283, Issue 1, 255-267, January 4, 2008

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Mechanism of Angiotensin II-induced Superoxide Production in Cells Reconstituted with Angiotensin Type 1 Receptor and the Components of NADPH Oxidase^*

Hyun Choi, Thomas L. Leto, László Hunyady^¶, Kevin J. Catt^||, Yun Soo Bae¹, and Sue Goo Rhee²

From the Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea, Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892, ^¶Department of Physiology, Semmelweis University, H-1088 Budapest, Hungary, and ^||Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892

The mechanism of angiotensin II (Ang II)-induced superoxide production was investigated with HEK293 or Chinese hamster ovary cells reconstituted with the angiotensin type 1 receptor (AT₁R) and NADPH oxidase (either Nox1 or Nox2) along with a pair of adaptor subunits (either NOXO1 with NOXA1 or p47^phox with p67^phox). Ang II enhanced the activity of both Nox1 and Nox2 supported by either adaptor pair, with more effective activation of Nox1 in the presence of NOXO1 and NOXA1 and of Nox2 in the presence of p47^phox and p67^phox. Expression of several AT₁R mutants showed that interaction of the receptor with G proteins but not that with β-arrestin or with other proteins (Jak2, phospholipase C-1, SH2 domain-containing phosphatase 2) that bind to the COOH-terminal region of AT₁R, was necessary for Ang II-induced superoxide production. The effects of constitutively active subunits of G proteins and of various pharmacological agents implicated signaling by a pathway comprising AT₁R, G_q/11, phospholipase C-β, and protein kinase C as largely, but not exclusively, responsible for Ang II-induced activation of Nox1 and Nox2 in the reconstituted cells. A contribution of G_12/13, phospholipase D, and phosphatidyl-inositol 3-kinase to Ang II-induced superoxide generation was also suggested, whereas Src and the epidermal growth factor receptor did not appear to participate in this effect of Ang II. In reconstituted cells stimulated with Ang II, Nox2 exhibited a more sensitive response than Nox1 to the perturbation of protein kinase C, phosphatidylinositol 3-kinase, or the small GTPase Rac1.

Received for publication, September 25, 2007 , and in revised form, October 29, 2007.

^* This study was supported in part by Korean Science and Engineering Foundation grants (National Honor Scientist Program Grant 2006-05106 and Grant FPR0502-470 of the 21C Frontier Functional Proteomics Projects (to S. G. R.)), the National Core Research Center program of Ministry of Science and Technology/Korea Science and Engineering Foundation Grant R15-2006-020-00000-0 (to Y. S. B.) through the Center for Cell Signaling and Drug Discovery Research at Ewha Womans University, National Research Laboratory Program Grant ROA-2007-000-20004-0 (to Y. S. B.), and by a Brain Korea21 grant (to H. C.). 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 may be addressed: Division of Life and Pharmaceutical Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul 120-750, Korea. Tel.: 82-2-3277-2729; Fax: 82-2-3277-3760; E-mail: baeys{at}ewha.ac.kr. ² To whom correspondence may be addressed: Division of Life and Pharmaceutical Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul 120-750, Korea. Tel.: 82-2-3277-2948; Fax: 82-2-3277-3760; E-mail: rheesg{at}ewha.ac.kr.

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