Microsomal Prostaglandin E Synthase-1 Deletion Suppresses Oxidative Stress and Angiotensin II–Induced Abdominal Aortic Aneurysm Formation
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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-iPF2α-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.
Received August 1, 2007; accepted January 2, 2008.