A Selective Antagonist Of Prostaglandin E Receptor Subtype 4 Attenuates Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a progressive disease that has an increasing prevalence with aging, but no effective pharmacological therapy to attenuate AAA progression is currently available. We reported that the prostaglandin E receptor EP4 plays roles in AAA progression. Here, we show the effect of CJ-42794, a selective EP4 antagonist, on AAA using two mouse models (angiotensin II- and CaCl2-induced AAAs) and human aortic smooth muscle cells isolated from AAA tissue. Oral administration of CJ-42794 (0.2mg/kg per day) for 4weeks significantly decreased AAA formation in ApoE(-/-) mice infused with angiotensin II (1g/kg per min), in which elastic fiber degradation and activations of matrix metalloproteinase (MMP)-2 and MMP-9 were attenuated. Interleukin-6 (IL-6) proteins were highly expressed in the medial layer of angiotensin II-induced mouse AAA tissues, whereas this expression was significantly decreased in mice treated with CJ-42794. AAA formation induced by periaortic CaCl2 application in wild-type mice was also reduced by oral administration of CJ-42794 for 4weeks. After oral administration of CJ-42794 beginning 2weeks after periaortic CaCl2 application and continuing for an additional 4weeks, the aortic diameter and elastic fiber degradation grade were significantly smaller in CJ-42794-treated mice than in untreated mice. Additionally, in smooth muscle cells isolated from human AAA tissues, stimulation of CJ-42794 inhibited PGE(2)-induced IL-6 secretion in a dose-dependent manner and decreased PGE(2)-induced MMP-2 activity. These data suggest that inhibition of EP4 has the potential to be a pharmacological strategy for attenuation of AAA progression.