Abstract 978: Microsomal PGE Synthase-1 Derived PGE2 Augments Angiotensin II-Induced Aortic Aneurysms
Microsomal (m) prostaglandin (PG) E2 synthase(S)-1, an enzyme that catalyzes the isomerization of the cyclooxygenase (COX) product, PGH2, into PGE2, is a major source of PGE2 in vivo. Deletion of mPGES-1 attenuates the inflammatory response and, unlike inhibition or disruption of COX-2, does not elevate blood pressure or predispose to thrombosis. The impact of mPGES-1 deletion on development of aneurysm was studied in angiotensin II (Ang II)-induced abdominal aortic aneurysm (AAA) model in mice lacking the low density lipoprotein receptor (LDLR KOs). Male mice deficient in both mPGES-1 and LDLR (DKOs) and littermate LDLR KOs were initiated a high fat diet at 6 months of age, followed one week later by continuous infusion of Ang II (1 μg/kg per minute) for additional 4 weeks. mPGES-1 deletion significantly decreased urinary excretion of a PGE2 metabolite (PGE-M: 11α-hydroxy-9, 15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid) in LDLR KOs. Ang II infusion augmented urinary PGE-M in LDLR KOs. Blood pressure increased significantly, but to a similar extent in the KO and DKO mice on infusion of AngII throughout the study. Sudden death due to rupture of abdominal aorta was both delayed and reduced in the DKOs. mPGES-1 deletion decreased both the incidence (KO: 87.5% [7:8] versus DKO: 27.3% [3:11]; P=0.02) of AAA formation and its severity (P<0.01), as reflected by the weight and maximal diameter of the abdominal aorta. These observations, especially when combined with our recent observation that enzyme deletion retards atherogenesis, suggest the potential utility of mPGES-1 inhibitors in the treatment of aneurysm.