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Inhibition Of Reactive Oxygen Species Attenuates Aneurysm Formation In A Murine Model

Jason N MacTaggart, Wanfen Xiong, Rebecca Knispel, Zhe Zhu, Yulong Lee, Yimin Sun, B. Timothy Baxter, Jason M Johanning ∙ University of Nebraska, Omaha, NE

Objective: Reactive oxygen species (ROS) and nitric oxide (NO) have been implicated in aneurysm pathogenesis but their origins remain ill defined. Our study was designed to assess the likely agents contributing to generation of these substances in a murine model of abdominal aortic aneurysm (AAA) formation.
Methods: AAA induction was performed by periaortic application of CaCl2. To investigate the cell of origin for superoxide anion (O2-) production, mice were treated with orally administered apocynin (NADPH oxidase inhibitor) or oxypurinol (xanthine oxidase inhibitor). Control mice were given water. To assess the source of NO production, iNOS knockout and wild type control animals underwent AAA induction. Aortic levels of NO metabolites, O2-, MMP 2 and 9 were measured
Results: In the absence of iNOS, mice are resistant to aneurysm induction and aortic levels of NO metabolites are significantly reduced(P<.05) with concomitant reduction in the expression of MMP 2 and 9. NADPH oxidase inhibition by apocynin resulted in lack of aneurysm formation (P<.05) whereas oxypurinol administration resulted in aneurysm formation not significantly different than wild type controls. O2-, MMP-2 and 9 levels were reduced in animals administered apocynin.
Conclusion: iNOS deficiency and NADPH oxidase inhibition suppresses aneurysm formation and results in reduction of MMP 2 and 9 in a murine aneurysm model. These studies suggest that the NADPH oxidase and iNOS are important pathways for ROS generation and AAA development.