Abstract 13612: An mPGES-1 Inhibitor Halts Abdominal Aortic Aneurysm Formation in Mice

Abstract

Background: Abdominal aortic aneurysm (AAA) is a deadly, permanent balloon of the aortic artery. Surgery is the only option available to patients, but it is risky. In addition, there are currently no FDA-approved pharmacological treatments for AAA available. Notably, microsomal prostaglandin E 2 synthase-1 (mPGES-1) is recognized as a promising target for development of a next generation of anti-inflammatory drugs. Through computational modeling and in vitro experiments, we have recently discovered a novel type of mPGES-1 inhibitors as possible anti-inflammatory drug candidates. Objectives: The purpose of this study was to assess the capability of an mPGES-1 inhibitor to alter the growth of AAA in the angiotensin (Ang)-II induced mouse model. Methods: For 28 days, 12-week-old male ApoE-/- were infused with Ang-II (1,000 ng/kg/min) plus either an mPGES-1 inhibitor (UK4b) starting day 7 (10 mg/kg SC, BID; N = 6) or no drug (control group, N = 9). Maximal aortic diameter was measured by ultrasound (Vevo 3100) on day 0 (baseline), 2, 5, 7, 12, 16, 21, and 28. Aorta tissues were collected after sacrifice on day 28 and measured. Results: On day 28, there was a significant difference between the maximal aortic diameters of the control and drug treated groups (2.08±0.22 mm, 1.34±0.02 mm; p < 0.005). Comparing day 28 in vivo and ex vivo measurements of aortas, there was no significant difference ( p = 0.898), validating the use of ultrasound as an in vivo measurement method in this study. Conclusions: In summary, the mPGES-1 inhibitor UK4b, was able to halt the progression of AAA in these mice. There was a significant difference in the size of aortas between the two groups which was validated by ex vivo assessment. These preliminary results show promise for the use of an mPGES-1 inhibitor in the treatment of AAA.