Vescular Mitochondrial Dysfunction as a Pathogenesis of Atherosclerosis

大量研究表明，氧化应激在心血管疾病的发病机制中起着关键作用。超氧阴离子是由分子氧的单价还原形成的。虽然超氧阴离子的产生涉及黄嘌呤氧化酶、NADH/NADPH氧化酶、脂氧合酶和一氧化氮合酶等多种酶，但体内最大的超氧阴离子工厂之一是线粒体。在患有线粒体疾病的患者中，血管并发症，不仅是中风，而且是冠状动脉疾病，通常在没有动脉粥样硬化危险因素的年轻人中观察到。线粒体疾病时，呼吸链底物利用缺陷或氧化-磷酸化偶联缺陷，导致超氧阴离子泄漏，在内皮细胞和血管平滑肌细胞内积聚异常线粒体。基础水平的内皮依赖性血管扩张功能丧失，可被抗氧剂…恢复线粒体疾病患者体内更多的抗坏血酸，提示氧化应激可能参与了过早的心血管疾病，抗氧化剂可能成为线粒体疾病的治疗工具。辅酶Q在线粒体电子传递链中起着至关重要的作用。辅酶Q的还原形式泛喹酚(CoQH2)是一种脂溶抗氧化剂。虽然在实验模型中补充辅酶QH2已被证明具有细胞保护作用，但仍不清楚内源性辅酶QH2是否在动脉粥样硬化的发生发展中起作用。这项研究的目的是在普通人群中调查辅酶QH2和临床下动脉粥样硬化之间的可能联系。在看似健康的受试者中，对冠状动脉危险因素进行了评估。用血流介导的肱动脉扩张评价内皮功能，用超声评价颈总动脉斑块积分。采用双抗体夹心法测定血浆辅酶QH2水平。出乎意料的是，单因素分析显示CoQH2与HOMA估计的代谢综合征危险因素、体重指数、甘油三酯、平均动脉压和胰岛素抵抗呈显著正相关。氧化应激的标志物--丙二醛修饰的低密度脂蛋白与辅酶QH2呈显著正相关。CoQH2与血流介导的血管扩张呈负相关，与斑块积分呈正相关。由经典危险因素组成的多元回归分析显示，CoQH2分别是血流介导的血管扩张和斑块积分的独立决定因素。因此，泛喹酚与代谢综合征受试者的内皮功能障碍和亚临床动脉粥样硬化之间存在矛盾的联系。我们的结果提示泛喹酚可能是代偿性升高，以预防动脉粥样硬化。较少

Numerous studies have demonstrated that oxidative stress plays a pivotal rote in the pathogenesis of cardiovascular dieseases. Superoxide anion is formed by univalent reduction of molecular oxygen. Although several enzymes are involved in the generation of superoxide anion, including xanthine oxidase, NADH/NADPH oxidase, lipoxygenase and nitric oxide synthase, one of the largest factories of superoxide anion in vivo is the mitochondrion. In patients with mitochondrial diseases, vascular complications, not only stroke but also coronary artery diseases, are commonly observed in young subjects without risk factors for atherosclerosis. Abnormal mitochondria, which have a defect in substrate utilization in the respiratory chain or of oxidation-phosphorylation coupling, leading to leakage of superoxide anions, are accumulated in the endothelium and vascular smooth muscle cells in mitochondrial diseases. Endothelium-dependent vasodilation was lost at basal level, which was restored by antioxi … More dant ascorbic acid in patients with mitochondrial diseases, suggesting that oxidative stress may be involved in premature cardiovascular diseases and antioxidants may become a therapeutic tool in mitochondrial diseases. Coenzyme Q plays an essential role in the mitochondrial electron-transport chain. Ubiquinol(CoQH2), the reduced form of coenzyme Q, is a lipid-soluble antioxidant. Although CoQH2 supplementation has been shown to have cell protective effects in experimental models, it remains unknown whether endogenous CoQH2 plays a role in the development of atherosclerosis. The aim of this study was to investigate a possible link between CoQH2 and subclincal atherosclerosis in a general population. In apparently healthy subjects, coronary risk factors were evaluated. Endothelial function was estimated by flow-mediated vasodilation of the brachial artery and plaque score of the common carotid artery were assessed by ultrasonography. Plasma levels of CoQH2 were determined by ELISA. Unexpectedly, univariate analyses revealed that CoQH2 was significantly and positively correlated with risk factors of metabolic sydrome, body mass index, triglyceride, mean arterial pressure, and insulin resistance estimated by HOMA. There was a significant positive relationship between CoQH2 and MDA-modified LDL, a marker of oxidative stress. CoQH2 was also inversely correlated with flow-mediated vasodilation and positively correlated with plaque score. Multiple regression analysis composing of classical risk factors revealed that CoQH2 was an independent determinant of flow-mediated vasodilation and plaque score, respectively. Thus, ubiquinol was paradoxically associated with endothelial dysfunction and subclinical atherosclerosis in subjects with metabolic syndrome. Our results suggest that ubiquinol may be compensatory elevated to prevent atherosclerosis. Less