title: Prostaglandin receptor EP4 in abdominal aortic aneurysms.
abstract: 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.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University and Kingston General Hospital, Kingston, Ontario, Canada.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Cao
authors.forename: Tim
authors.initials: T
authors.lastname: St Amand
authors.forename: XinZhi
authors.initials: X
authors.lastname: Li
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Yoon
authors.forename: Carol P
authors.initials: CP
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Song
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Peter M
authors.initials: PM
authors.lastname: Brown
authors.forename: David T
authors.initials: DT
authors.lastname: Zelt
authors.forename: Colin D
authors.initials: CD
authors.lastname: Funk
mesh_terms: D000328:Adult; D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000503:physiopathology* / Q000517:prevention & control; D001019:Aortic Rupture / Q000517:prevention & control; D050197:Atherosclerosis / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014463:Ultrasonography
chemical_list: C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D009281:Naphthalenes; D010654:Phenylbutyrates; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000804:Angiotensin II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2