Vescular Mitochondrial Dysfunction as a Pathogenesis of Atherosclerosis

血管线粒体功能障碍是动脉粥样硬化的发病机制

• 批准号: 15590782
• 负责人: MATSUOKA Hidehiro
• 金额: $ 2.24万
• 依托单位: Kurume University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590782/
• 关键词: atherosclerosis; endothelium; oxidative stress; mitochondria; antioxidant; nitric oxide; reactive oxygen spieces

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

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。虽然有几种酶参与超氧阴离子的生成，包括黄嘌呤氧化酶、NADH/NADPH氧化酶、脂肪加氧酶和一氧化氮合酶，但体内最大的超氧阴离子工厂之一是线粒体。在线粒体疾病患者中，血管并发症，不仅是中风，还有冠状动脉疾病，通常在没有动脉粥样硬化危险因素的年轻受试者中观察到。线粒体疾病时，内皮细胞和血管平滑肌细胞内积聚了异常线粒体，这些线粒体在呼吸链中利用底物或氧化-磷酸化偶联中存在缺陷，导致超氧阴离子泄漏。在线粒体疾病患者中，抗坏血酸含量较高，提示氧化应激可能与早期心血管疾病有关，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重要作用。泛醇（CoQH2）是辅酶Q的还原形式，是一种脂溶性抗氧化剂。尽管CoQH2补充在实验模型中已被证明具有细胞保护作用，但内源性CoQH2是否在动脉粥样硬化的发展中发挥作用仍不清楚。本研究的目的是研究CoQH2与普通人群亚临床动脉粥样硬化之间的可能联系。在表面健康的受试者中，评估冠状动脉危险因素。通过血流介导的肱动脉血管舒张评估内皮功能，超声评估颈总动脉斑块评分。ELISA法检测血浆CoQH2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、体重指数、甘油三酯、平均动脉压和胰岛素抵抗的危险因素显著正相关。CoQH2与mda修饰的低密度脂蛋白（一种氧化应激标志物）之间存在显著正相关。CoQH2与血流介导的血管舒张呈负相关，与斑块评分呈正相关。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舒张和斑块评分的独立决定因素。因此，泛醇与代谢综合征患者的内皮功能障碍和亚临床动脉粥样硬化有矛盾的关系。我们的研究结果表明，泛醇可能通过补偿性升高来预防动脉粥样硬化。少

项目成果

動脈硬化と血管内皮機能

动脉硬化与血管内皮功能

• 发表时间: 2004
• 期刊: Vascular Lab 2
• 作者: 松岡秀洋

Regulation of cytokine-induced nitric oxide synthesis by asymmetric dimethylarginine : Role of dimethylarqinine dimethylaminohydrolase.

不对称二甲基精氨酸调节细胞因子诱导的一氧化氮合成：二甲基精氨酸二甲氨基水解酶的作用。

• 发表时间: 2003
• 期刊: Circ Res 92
• 作者: Ueda S;Matsuoka H et al.
• 通讯作者: Matsuoka H et al.

血管内皮障害と治療効果-高血圧

血管内皮疾病及其治疗效果——高血压

• 发表时间: 2004
• 期刊: 治療学 38
• 作者: Kumagai K;Nakashima H;Saku K.;Kawada T et al.;松岡秀洋
• 通讯作者: 松岡秀洋

高脂血圧ナビゲーター

高脂血症导航仪

• 发表时间: 2003
• 作者: Seiji Ueda;Seiya Kato;Hidehiro Matsuoka;Masumi Kimoto;Seiya Okuda;Minoru Morimatsu;Tsutomu Imaizumi;松岡秀洋(分担執筆);松岡秀洋 他
• 通讯作者: 松岡秀洋 他

血管の老化のメカニズム

血管老化的机制

• 发表时间: 2004
• 期刊: モダンフィジシャン 24
• 作者: Taguchi A;Matsuyama T;Moriwaki H;Hayashi T;Hayashida K;Nagatsuka K;Todo K;Mori K;Stern D;Soma T;Naritomi N;Kawada T et al.;松岡秀洋
• 通讯作者: 松岡秀洋