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(Hypertension. 2008;52:952.)
© 2008 American Heart Association, Inc.

Original Articles

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E₂ Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

Zhanjun Jia; Xiaohua Guo; Hui Zhang; Mong-Heng Wang; Zheng Dong; Tianxin Yang

From the Department of Internal Medicine (Z.J., X.G., H.Z., T.Y.), University of Utah and Veterans’ Affairs Medical Center, Salt Lake City; Departments of Physiology (M.-H.W.) and Cellular Biology and Anatomy (Z.D.), Medical College of Georgia, Augusta; and Medical Research Service (Z.D.), Veterans’ Affairs Medical Center, Augusta, Ga.

Correspondence to Tianxin Yang, University of Utah and VA Medical Center, 30 N 1900 E, Room 4R312, Salt Lake City, UT 84132. E-mail tianxin.yang{at}hsc.utah.edu

Prostaglandin (PG) E₂ has an established role in the regulation of vascular tone and reactivity. The present study examined the role and mechanism of microsomal PG synthase-1 (mPGES-1) in vascular response to angiotensin II (Ang II) infusion. A 7-day Ang II infusion at 0.35 mg/kg per day via osmotic minipump had no obvious effect on mean arterial blood pressure in mPGES-1^+/+ mice but induced a marked hypertensive response in mPGES-1^–/– mice, associated with a parallel increase in urinary 8-isoprostane excretion and aortic NADPH oxidase activity and mRNA expression of p47^phox, gp91^phox, and Nox1. The hypertension in mPGES-1^–/– mice was completely prevented by Tempol treatment and was fully restored on termination of the antioxidant. Apocynin induced a similar blood pressure–lowering effect as Tempol. The Ang II infusion induced mRNA expression of mPGES-1, as well as mPGES-2 and cytosolic PGE synthase in the aortas as assessed by real-time RT-PCR. Immunohistochemistry revealed remarkably enhanced immunoreactivity of mPGES-1 mostly in vascular smooth muscle cells. In cultured vascular smooth muscle cells, Ang II exerted a direct stimulatory effect on reactive oxygen species production, NADPH oxidase activity, and expression of p47^phox, gp91^phox, and Nox1 that were all inhibited by PGE₂. The –/– mice also exhibited enhanced renal hemodynamic response to acute Ang II infusion at 150 nmol/kg per minute via a jugular vein over a period of 40 minutes. These results suggest that mPGES-1–derived PGE₂ buffers Ang II–induced vasoconstriction via inhibition of NADPH oxidase–dependent reactive oxygen species production.

Key Words: mPGES-1 • angiotensin II • mean arterial pressure • oxidative stress • NADPH oxidase