Abstract 12641: Therapeutic Effect of EP4 Antagonist on Advanced Abdominal Aortic Aneurysm
Introduction: No pharmacological therapy has been available for advanced aortic aneurysm (AA), a life-threatening disease. We have reported that inhibition of the prostaglandin E2 (PGE2) receptor EP4 decreased the onset of AA when angiotensin II (ATII) was infused to mice. In this study, we have examined whether EP4 antagonist (EP4ant) prevents the progression of advanced AA in mice. Effect of PGE2 was also examined in human AA tissues.
Methods: ApoE-deficient mice were administrated with ATII (1μg/kg/min) for 4 weeks, followed by oral administration of EP4ant (ONO-AE3-208, 0.01mg/kg/day) or saline for 4 weeks (n=12). Sham group was infused with saline, followed by saline intake (n=6). Elastic fiber formation was graded by Elastica stain. Human AA tissues were obtained at surgery with informed consents (n=3). The AA tissues were cultured in DMEM in the presence or absence of PGE2 for 24 h. Secreted proteins were quantified by LC/MS/MS using iTRAQ reagents.
Results: ATII infusion for 4 weeks was sufficient to induce advanced AA in ApoE-deficient mice. Cyclooxygenase-2 (COX-2) protein was highly and similarly expressed in both saline- and EP4ant-treated mice (3.2±0.5-and 3.5±0.6-fold vs. sham, p≤0.01, respectively). In contrast, elastic fiber degradation was much less in EP4ant group (1.4±0.2-fold vs. sham) than in saline control (2.4±0.3-fold vs. sham, p≤0.01) while aortic diameter was similar between the two. ATII administration is known to decrease lysyl oxidase expression, which cross-links elastin to promote elastogenesis. Immunohistochemistry revealed that EP4ant restored lysyl oxidase expression by 54±12% (p≤0.01). Upregulation of matrixmetalloproteinase-2 (MMP2) and-9 protein expressions were completely inhibited by EP4ant. Furthermore, a comprehensive proteomic analysis of human AA showed that PGE2 increased interleukin-8 and-6, neutrophil elastase, and MMP2 (3.9±1.5-, 2.3±0.8-, 1.5±0.3-, and 1.2±0.2-fold, respectively), suggesting that PGE2 promotes inflammation and proteolysis in progressing human AA.
Conclusions: These data suggest that EP4ant may exhibit therapeutic effect on advanced AA where COX-2 is activated. Human data also showed that inhibition of PGE2-mediated pathway may serve a new therapeutic strategy.
- © 2013 by American Heart Association, Inc.