Prostaglandin receptor EP4 in abdominal aortic aneurysms.
| Autor: | Cao RY; Department of Biomedical and Molecular Sciences, Queen's University and Kingston General Hospital, Kingston, Ontario, Canada., St Amand T, Li X, Yoon SH, Wang CP, Song H, Maruyama T, Brown PM, Zelt DT, Funk CD |
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| Jazyk: | angličtina |
| Zdroj: | The American journal of pathology [Am J Pathol] 2012 Jul; Vol. 181 (1), pp. 313-21. Date of Electronic Publication: 2012 May 15. |
| DOI: | 10.1016/j.ajpath.2012.03.016 |
| Abstrakt: | 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 E(2)-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. (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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