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.

A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model

“…Our current findings align with our previously published work demonstrating analgesic and anti-inflammatory effects of UK4b through regulation of PGE 2 37 , 46 . Similarly, our current study shows that PGE 2 concentrations were also observed to be significantly decreased in UK4b treated mice.…”

“…We examined two biomarkers to better understand the downstream effects of mPGES-1 inhibition in relation to AAA progression. The first, PGE 2 , is the enzymatic product of mPGES-1 and a key inflammatory mediator that has been implicated in AAA pathogenesis 7 , 20 , 23 , 36 , 43 – 46 . We measured plasma PGE 2 concentrations in study mice from all groups on days 0, 7, and 28 (Fig.…”