Angiotensin II, oxidative stress, and aneurysm formation

血管紧张素 II、氧化应激和动脉瘤形成

• 批准号: 7018548
• 负责人: Neal L Weintraub
• 金额: $ 36.01万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-16 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7018548
• 关键词: NAD(P)H dehydrogenase; angiotensin II; aorta aneurysm; enzyme activity; free radical oxygen; histology; hydrogen peroxide; laboratory mouse; lipid peroxides; oxidative stress; superoxide dismutase; superoxides

DESCRIPTION (provided by applicant): Abdominal aortic aneurysms (AAA) occur in approximately 3% of humans > 65 years of age and are characterized by localized structural deterioration of the aortic wall, leading to progressive aortic dilation, The morbidity and mortality associated with AAA are considerable. Surprisingly, however, little is known about the mechanisms responsible for aneurysm formation and progression. Recent histological studies in humans indicate that AAA are highly inflammatory in nature. The inflammatory response is associated with death of smooth muscle cells (SMC) and degradation of matrix proteins by matrix metalloproteinases (MMP) that causes weakening of the aortic wall, and, consequently, dilation. Given that reactive oxygen species (ROS) are produced during inflammation and can induce SMC death and MMP activation, we hypothesize that ROS play a pivotal role in AAA formation. As an initial step to investigate this hypothesis, we examined human aneurysm tissue removed at the time of elective AAA repair. Our studies indicate that levels of superoxide and lipid peroxidation products, an index of tissue injury caused by oxidative stress, are markedly increased in AAA as compared with adjacent, non-aneurysmal aortic tissue obtained from the same patients. We also detected increased expression and activity of NAD(P)H oxidase, a superoxide-generating enzyme, in AAA. Whether or not ROS contribute to the pathogenesis of AAA, however, remains to be determined. An experimental model of aneurysm formation has recently been developed in which angiotensin II is infused into hyperlipidemic male mice. After 28 days, the mice develop AAA with histologic and pathological features that resemble AAA in humans. Angiotensin II is known to induce aortic inflammation and production of superoxide through activation of NAD(P)H oxidase, which is thought to play a role in vascular disease in humans. Preliminary data using this model indicate that levels of superoxide in the aorta of these mice are markedly increased in response to infusion of angiotensin II, preceding the formation of AAA. Here, we propose to employ a combination of pharmacological and genetic approaches to modulate ROS and NAD(P)H oxidase, and to modulate the Rho/ROCK signaling pathway, in order to investigate the role of oxidative stress in AAA formation. Our findings could have important implications with regard to the treatment of AAA in humans.

描述（由申请人提供）：腹主动脉瘤（AAA）发生在大约3％的人类> 65岁以上，其特征是主动脉壁的局部结构恶化，导致渐进性主动脉膨胀，与AAA相关的发病率和死亡率是相当大的。然而，令人惊讶的是，对负责动脉瘤形成和进展的机制知之甚少。人类的最新组织学研究表明，AAA本质上是高度炎症的。炎症反应与平滑肌细胞（SMC）的死亡以及基质蛋白通过基质金属蛋白酶（MMP）降解，从而导致主动脉壁的减弱，从而降低。鉴于活性氧（ROS）是在炎症过程中产生的，并可能诱导SMC死亡和MMP激活，因此我们假设ROS在AAA形成中起关键作用。作为研究这一假设的第一步，我们检查了在选择性AAA修复时去除的人类动脉瘤组织。我们的研究表明，与从同一患者获得的相邻的非干扰素主动脉组织相比，AAA的超氧化物和脂质过氧化产物的水平是由氧化应激引起的指数显着增加。我们还检测到AAA中NAD（P）H氧化酶（一种超氧化物生成酶）的表达和活性增加。然而，ROS是否有助于AAA的发病机理，尚待确定。最近已经开发了一种动脉瘤形成的实验模型，在该模型中，血管紧张素II被注入高脂雄性小鼠中。 28天后，小鼠开发具有类似于人类AAA的组织学和病理特征的AAA。已知血管紧张素II通过激活NAD（P）H氧化酶诱导主动脉炎症和超氧化物的产生，该酶在人类的血管疾病中起着作用。使用该模型的初步数据表明，这些小鼠主动脉中的超氧化物水平显着增加，因为血管紧张素II在AAA的形成之前，这些小鼠的氧化水平显着增加。在这里，我们建议采用药理和遗传方法的组合来调节ROS和NAD（P）H氧化酶，并调节Rho/Rock信号传导途径，以研究氧化应激在AAA形成中的作用。我们的发现在人类中对AAA的治疗可能具有重要意义。