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Vascular biology, atherosclerosis, and endothelium biology
Prostaglandin Receptor EP4 in Abdominal Aortic Aneurysms

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Abdominal aortic aneurysm (AAA) pathogenesis is distinguished by vessel wall inflammation. Cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1, key components of the most well-characterized inflammatory prostaglandin pathway, contribute to AAA development in the 28-day angiotensin II infusion model in mice. In this study, we used this model to examine the role of the prostaglandin E receptor subtype 4 (EP4) and genetic knockdown of COX-2 expression (70% to 90%) in AAA pathogenesis. The administration of the prostaglandin receptor EP4 antagonist AE3-208 (10 mg/kg per day) to apolipoprotein E (apoE)–deficient mice led to active drug plasma concentrations and reduced AAA incidence and severity compared with control apoE-deficient mice (P < 0.01), whereas COX-2 genetic knockdown/apoE-deficient mice displayed only a minor, nonsignificant decrease in incidence of AAA. EP4 receptor protein was present in human and mouse AAA, as observed by using Western blot analysis. Aortas from AE3-208–treated mice displayed evidence of a reduced inflammatory phenotype compared with controls. Atherosclerotic lesion size at the aortic root was similar between all groups. In conclusion, the prostaglandin E2–EP4 signaling pathway plays a role in the AAA inflammatory process. Blocking the EP4 receptor pharmacologically reduces both the incidence and severity of AAA in the angiotensin II mouse model, potentially via attenuation of cytokine/chemokine synthesis and the reduction of matrix metalloproteinase activities.

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Supported by a grant from the Canadian Institutes of Health Research (MOP-93689 to C.D.F.). C.D.F. is the recipient of a Tier I Canada Research Chair in Molecular, Cellular and Physiological Medicine and is a Career Investigator of the Heart and Stroke Foundation of Ontario.

Disclosures: T.M. is employed by Ono Pharmaceutical Co., Ltd., which supplied the EP4 antagonist, AE3-208, used in these studies.

Supplemental material for this article can be found on http://ajp.amjpathol.org or at http://dx.doi.org/10.1016/j.ajpath.2012.03.016.