title: Inhibition of reactive oxygen species attenuates aneurysm formation in a murine model.
abstract: Reactive oxygen species (ROS) are increased in human abdominal aortic aneurysms (AAA). NADPH oxidases are the predominant source of superoxide anion (O(2)(-)) in the vasculature. Inducible nitric oxide synthase (iNOS) produces a significant amount of nitric oxide (NO) during inflammatory processes. We hypothesized that ROS produced by NADPH oxidases and iNOS played an important role in aneurysm formation. We examined this hypothesis using selective blockade of NADPH oxidases and iNOS in a murine model of AAA. Mice, including C57BL/6, iNOS knockout (iNOS(-/-)) mice, and its background matched control (C57BL/6), underwent AAA induction by periaortic application of CaCl(2). Aortic diameter was measured at aneurysm induction and harvest. Beginning 1 week prior to aneurysm induction and continuing to aortic harvest 6 weeks later, one group of the C57BL/6 mice were treated with orally administered apocynin (NADPH oxidase inhibitor). Control mice were given water. The mean diameter and change in diameter of each group were compared with concurrent controls. Aortic levels of the NO metabolite, NO(x) (NO(2) and NO(3)), were significantly increased in CaCl(2)-treated wild type mice. INOS(-/-) mice were partly resistant to aneurysm induction. This was associated with reduced expression of matrix metalloproteinase (MMP)-2 and MMP-9 and decreased production of NO(x) in the aortic tissues. Inhibition of NADPH oxidase by apocynin also blocked aneurysm formation. In conclusion, both iNOS deficiency and NADPH oxidase inhibition suppressed aneurysm formation in association with decreased NO(x) levels. These studies suggest that both NADPH oxidase and iNOS pathways contribute to ROS production and AAA development.
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-7690, USA. wxiong@unmc.edu
authors.forename: Wanfen
authors.initials: W
authors.lastname: Xiong
authors.forename: Jason
authors.initials: J
authors.lastname: Mactaggart
authors.forename: Rebecca
authors.initials: R
authors.lastname: Knispel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Worth
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhu
authors.forename: Yulong
authors.initials: Y
authors.lastname: Li
authors.forename: Yimin
authors.initials: Y
authors.lastname: Sun
authors.forename: B Timothy
authors.initials: BT
authors.lastname: Baxter
authors.forename: Jason
authors.initials: J
authors.lastname: Johanning
mesh_terms: D000098:Acetophenones / Q000378:metabolism; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017382:Reactive Oxygen Species
chemical_list: D000098:Acetophenones; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C056165:acetovanillone; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9