title: Inhibition of EP4 signaling attenuates aortic aneurysm formation.
abstract: BACKGROUND
  Aortic aneurysm is a common but life-threatening disease among the elderly, for which no effective medical therapy is currently available. Activation of prostaglandin E(2) (PGE(2)) is known to increase the expression of matrix metalloproteinase (MMP) and the release of inflammatory cytokines, and may thus exacerbate abdominal aortic aneurysm (AAA) formation. We hypothesized that selective blocking of PGE(2), in particular, EP4 prostanoid receptor signaling, would attenuate the development of AAA.
  
  
  RESULTS
  Immunohistochemical analysis of human AAA tissues demonstrated that EP4 expression was greater in AAA areas than that in non-diseased areas. Interestingly, EP4 expression was proportional to the degree of elastic fiber degradation. In cultured human aortic smooth muscle cells (ASMCs), PGE(2) stimulation increased EP4 protein expression (1.4 ± 0.08-fold), and EP4 stimulation with ONO-AE1-329 increased MMP-2 activity and interleukin-6 (IL-6) production (1.4 ± 0.03- and 1.7 ± 0.14-fold, respectively, P<0.05). Accordingly, we examined the effect of EP4 inhibition in an ApoE(-/-) mouse model of AAA infused with angiotensin II. Oral administration of ONO-AE3-208 (0.01-0.5 mg/kg/day), an EP4 antagonist, for 4 weeks significantly decreased the formation of AAA (45-87% reduction, P<0.05). Similarly, EP4(+/-)/ApoE(-/-) mice exhibited significantly less AAA formation than EP4(+/+)/ApoE(-/-) mice (76% reduction, P<0.01). AAA formation induced by periaortic CaCl(2) application was also reduced in EP4(+/-) mice compared with wild-type mice (73% reduction, P<0.001). Furthermore, in human AAA tissue organ cultures containing SMCs and macrophages, doses of the EP4 antagonist at 10-100 nM decreased MMP-2 activation and IL-6 production (0.6 ± 0.06- and 0.7 ± 0.06-fold, respectively, P<0.05) without increasing MMP-9 activity or MCP-1 secretion. Thus, either pharmacological or genetic EP4 inhibition attenuated AAA formation in multiple mouse and human models by lowering MMP activity and cytokine release.
  
  
  CONCLUSIONS
  An EP4 antagonist that prevents the activation of MMP and thereby inhibits the degradation of aortic elastic fiber may serve as a new strategy for medical treatment of AAA.
authors.affiliation: Cardiovascular Research Institute, Yokohama City University, Yokohama, Japan. utako@yokohama-cu.ac.jp
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.forename: Ryo
authors.initials: R
authors.lastname: Ishiwata
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Jin
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kato
authors.forename: Orie
authors.initials: O
authors.lastname: Suzuki
authors.forename: Huiling
authors.initials: H
authors.lastname: Jin
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Syun
authors.initials: S
authors.lastname: Kumagaya
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Katayama
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
authors.forename: Motohiko
authors.initials: M
authors.lastname: Sato
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Aoki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Munetaka
authors.initials: M
authors.lastname: Masuda
authors.forename: Susumu
authors.initials: S
authors.lastname: Minamisawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D046509:Tissue Culture Techniques; D015854:Up-Regulation / Q000235:genetics
chemical_list: C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D001057:Apolipoproteins E; D015850:Interleukin-6; D061965:Matrix Metalloproteinase Inhibitors; D009281:Naphthalenes; D010654:Phenylbutyrates; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000804:Angiotensin II; D020778:Matrix Metalloproteinase 2