Xiong Wanfen, Mactaggart Jason, Knispel Rebecca, Worth Jennifer, Zhu Zhen, Li Yulong, Sun Yimin, Baxter B Timothy, Johanning Jason
Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-7690, USA.
Atherosclerosis. 2009 Jan;202(1):128-34. doi: 10.1016/j.atherosclerosis.2008.03.029. Epub 2008 Apr 22.
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.
活性氧（ROS）在人类腹主动脉瘤（AAA）中水平升高。NADPH氧化酶是血管系统中超氧阴离子（O₂⁻）的主要来源。诱导型一氧化氮合酶（iNOS）在炎症过程中产生大量一氧化氮（NO）。我们推测，NADPH氧化酶和iNOS产生的ROS在动脉瘤形成中起重要作用。我们在AAA小鼠模型中通过选择性阻断NADPH氧化酶和iNOS来检验这一假设。包括C57BL/6、iNOS基因敲除（iNOS⁻/⁻）小鼠及其背景匹配的对照（C57BL/6）在内的小鼠，通过主动脉周围应用氯化钙诱导AAA形成。在诱导动脉瘤形成和收获时测量主动脉直径。从诱导动脉瘤形成前1周开始，持续到6周后收获主动脉，一组C57BL/6小鼠口服载脂蛋白（NADPH氧化酶抑制剂）进行治疗。对照小鼠给予水。将每组的平均直径和直径变化与同期对照进行比较。在氯化钙处理的野生型小鼠中，NO代谢产物NOₓ（NO₂和NO₃）的主动脉水平显著升高。iNOS⁻/⁻小鼠对动脉瘤诱导有部分抗性。这与主动脉组织中基质金属蛋白酶（MMP）-2和MMP-9的表达降低以及NOₓ的产生减少有关。载脂蛋白对NADPH氧化酶的抑制也阻止了动脉瘤的形成。总之，iNOS缺乏和NADPH氧化酶抑制均与NOₓ水平降低相关，从而抑制了动脉瘤的形成。这些研究表明，NADPH氧化酶和iNOS途径均有助于ROS的产生和AAA的发展。
