Source
Institute for Translational Medicine and Therapeutics, 153 Johnson Pavilion, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.
Abstract
BACKGROUND:
Microsomal prostaglandin (PG) E(2) synthase-1 (mPGES-1) catalyzes isomerization of the cyclooxygenase product PGH(2) into PGE(2). 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 microg/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-iPF(2alpha)-VI (which reflects lipid peroxidation in vivo) and the major metabolite of PGE(2) (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 PGD(2) and PGI(2) metabolites, reflecting rediversion of the accumulated PGH(2) 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.