Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin e 2 Synthase Type 1-Deficient Mice: Attenuation by Aspirin

Abstract

BACKGROUND: Inflammation plays an important role in formation and rupture of intracranial aneurysms. Expression of microsomal prostaglandin E 2 (PGE 2) synthase type 1 (mPGES-1) is increased in the wall of intracranial aneurysms in humans. PGE 2, a by-product of mPGES-1, is associated with inflammation and cerebrovascular dysfunction. OBJECTIVE: To test the hypothesis that deletion of mPGES-1 decreases the formation and rupture of intracranial aneurysms in a murine model. METHODS: Intracranial aneurysms were induced in wild-type and mPGES-1 knockout (mPGES-1 KO) mice by using a combination of deoxycorticosterone acetate-salt-induced hypertension and intracranial injection of elastase in the basal cistern. Prevalence of aneurysms, subarachnoid hemorrhage, and mortality were assessed. We also tested the effects of administration of aspirin (6 mg/kg/d) by gavage and PGE 2 (1 mg/kg/d) by subcutaneous infusion. RESULTS: Systolic blood pressure and prevalence of aneurysm were similar in wild-type and mPGES-1 KO mice. However, mortality and the prevalence of subarachnoid hemorrhage were markedly increased in mPGES-1 KO mice (P