Abstract 9480: Contrasting Effects of Imidapril and Losartan on Matrix Metalloproteinase in Human Abdominal Aortic Aneurysm

Abstract

Background: Abdominal aortic aneurysm (AAA) is characterized is characterized by the destruction of tissue architecture due to chronic inflammation. Emerging clinical evidence showed the effectiveness of angiotensin-converting enzyme inhibitor (ACEI) on the prognosis of AAA more than angiotensin II receptor blockers (ARB). We investigated the effects of an ACEI, imidapril and an ARB, losartan, on the activity of matrix metalloproteinase (MMP)-2 and -9 in human and murine AAA tissues. Methods: Five specimens were obtained as a whole abdominal aortic tissue (from proximal margin to distal margin). A whole sample was categorized into three zone; zones of margin, middle, and maximum diameter. Whole tissues were cut into around one inch of pieces, and then characterized for the histological parameters. The activities of MMPs were detected on AAA tissues by in situ gelatin zymography. Results: The MMP activities were increased in middle zone compared with other zones. The in sizu gelatin zymograhy showed that MMP activities on human AAA tissue in middle zone were significantly reduced by adding imidapril compared with losartan into reaction reagents. In addition, in vitro experiments showed that activities of human MMP-9 in a tube were significantly inhibited by imidapril, but not losartan in dose dependent manner. Next, we investigated the effects of imidapril (10mg/kg/day), losartan (10mg/kg/day), and hydralazine (10mg/kg/day) on CaCl 2 -induced AAA in mice. Six week after CaCl 2 -treatment, imidapril significantly prevented the enlargement of aorta compared to treatments with losartan and hydralazine (28%, 60% and 84%, respectively, p<0.01), while blood pressures were similarly lowered among three groups. The elevated expressions of MCP-1 and TNF-alpha and the recruitment of macrophages to AAA lesion were significantly reduced in imidapril-treated mice compared to losartan and hydralazine-treated mice. The in situ gelatin zymographies in mice also showed that lower MMP activities in AAA in imidapril treated mice compared with losartan and hydralazine treated mice. Conclusion: The direct inhibitory effect of imidapril on gelatinolytic activities may contribute to the protection of AAA.