Angiotensin II, oxidative stress, and aneurysm formation

描述（由申请人提供）：腹主动脉瘤（AAA）发生在65岁以下约3%的人群中，其特征是局部主动脉壁结构恶化，导致主动脉进行性扩张，与AAA相关的发病率和死亡率相当高。然而，令人惊讶的是，人们对动脉瘤形成和发展的机制知之甚少。最近对人类的组织学研究表明，AAA本质上是高度炎症性的。炎症反应与平滑肌细胞（SMC）死亡和基质金属蛋白酶（MMP）降解基质蛋白有关，导致主动脉壁减弱，从而导致扩张。鉴于炎症过程中产生活性氧（ROS）并可诱导SMC死亡和MMP激活，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修复时切除的人动脉瘤组织。我们的研究表明，与来自同一患者的邻近非动脉瘤性主动脉组织相比，AAA的超氧化物和脂质过氧化产物水平（氧化应激引起的组织损伤指标）明显增加。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是否参与AAA的发病机制仍有待确定。血管紧张素II输注到高脂血症雄性小鼠中，最近建立了动脉瘤形成的实验模型。28天后，小鼠发展为AAA，其组织学和病理特征与人类AAA相似。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，这被认为在人类血管疾病中发挥作用。该模型的初步数据表明，在AAA形成之前，这些小鼠的主动脉中超氧化物水平在血管紧张素II输注的反应中显着增加。在这里，我们建议采用药理学和遗传学相结合的方法来调节ROS和NAD(P)H氧化酶，并调节Rho/ROCK信号通路，以研究氧化应激在AAA形成中的作用。我们的发现可能对人类AAA的治疗有重要意义。

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.