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(Circulation. 2008;117:1302-1309.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Microsomal Prostaglandin E Synthase-1 Deletion Suppresses Oxidative Stress and Angiotensin II–Induced Abdominal Aortic Aneurysm Formation

Miao Wang, PhD; Eric Lee, MS; Wenliang Song, MD; Emanuela Ricciotti, PhD; Daniel J. Rader, MD; John A. Lawson, BS; Ellen Puré, PhD; Garret A. FitzGerald, MD

From the Institute for Translational Medicine and Therapeutics, University of Pennsylvania (M.W., W.S., E.R., D.J.R., J.A.L., G.A.F.); and the Wistar Institute (E.L., E.P.), Philadelphia, Pa.

Correspondence to Garret A. FitzGerald, MD, Institute for Translational Medicine and Therapeutics, 153 Johnson Pavilion, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104. E-mail garret{at}spirit.gcrc.upenn.edu

Received August 1, 2007; accepted January 2, 2008.

Background— Microsomal prostaglandin (PG) E₂ synthase-1 (mPGES-1) catalyzes isomerization of the cyclooxygenase product PGH₂ into PGE₂. Deletion of mPGES-1 modulates experimentally evoked pain and inflammation and retards atherogenesis. The role of mPGES-1 in abdominal aortic aneurysm is unknown.

Methods and Results— The impact of mPGES-1 deletion on formation of angiotensin II–induced abdominal aortic aneurysm was studied in mice lacking low-density lipoprotein receptor (LDLR^–/–). Male mice deficient in both mPGES-1 and LDLR (mPGES-1^–/– LDLR^–/–) and littermate LDLR^–/– mice were initiated on a high-fat diet at 6 months of age, followed 1 week later by continuous infusion of angiotensin II (1 µg/kg per minute) for an additional 4 weeks. Angiotensin II infusion upregulated aortic expression of cyclooxygenase-2 and mPGES-1, increased aortic macrophage recruitment and vascular nitrotyrosine staining (which reflects local oxidative stress), and augmented urinary excretion of the isoprostane 8,12-iso-iPF₂-VI (which reflects lipid peroxidation in vivo) and the major metabolite of PGE₂ (PGE-M). Deletion of mPGES-1 decreased both the incidence (87.5% versus 27.3%; P=0.02) and the severity of abdominal aortic aneurysm and depressed the aortic and systemic indices of oxidative stress. Deletion of mPGES-1 also depressed urinary PGE-M, whereas it augmented excretion of PGD₂ and PGI₂ metabolites, reflecting rediversion of the accumulated PGH₂ substrate in the double knockouts.

Conclusions— Deletion of mPGES-1 protects against abdominal aortic aneurysm formation induced by angiotensin II in hyperlipidemic mice, coincident with a reduction in oxidative stress. The potential efficacy of selective inhibition of mPGES-1 in preventing or retarding aneurysm formation warrants further investigation.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 117: 1247. [Full Text]