Research on the contribution of oxidative stress to the pathogenesis of cardiovascular diseases associated with life-styles

氧化应激在生活方式相关心血管疾病发病机制中的作用研究

基本信息

批准号：
18390204
负责人：
YOSHIDA Ken-ichi
金额：
$ 9.86万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

1) Contribution of 4-Hydroxynonenal (HNE) and Nitorotyrosine (NT) to pathogenesis of life-style diseases Post-menopausal women showed greater and sustained increase in blood pressure and serum HNE than young women after a psychological stress Color Word Test. Similarly, ovariectomized (OVX) rat showed greater increase in serum NT and blood pressure (BP). Additionally, in spontaneously hypertensive rat (SHR), treadmill exercise suppressed the onset of hypertension and increases in NT and HNE in serum and aorta. These results demonstrated that oxidative stress is involved in the pathogenesis of postmenopausal cardiovascular diseases and hypertension. In OVX rat, visceral fat and insulin resistance were increased, whereas the endothelial nitric oxide synthase (eNOS) expression was decreased in the mesentery. These results suggest that OVX rat provide a model of metabolic syndrome.2) Contribution of HNE to the pathogenesis of inflammation After LPS administration, the serum HNE in the rat increased transiently from the superoxide derived from monocyte NADPH oxidase. In the intestinal mucosa, IgA was secreted post-LPS from plasma cells after HNE modification and polymerization. Additionally, CYP and NADPH oxidase generate superoxide and HNE in the endoplasmic reticulum, thereby contributing to HNE modification and limited proteolysis of GRP78.3) Connexin 43 (Cx43) up-regulates in cardiomyocytes and contributes to injury and death in ischemia-reperfusion. Coronary artery occlusion in the rat increases Cx43 expression and gap junction interecellular communication, thereby contributing to the propagation of contraction band necrosis and infarct development. In the cultured cardiomyocytes, the transient Cx43 up-regulation during ischemia induces Ca^<2+> influx via hemichannel and cell death.

1）4-羟基壬烯醛（HNE）和硝基酪氨酸（NT）对生活方式疾病发病机制的贡献绝经后妇女在心理压力色词测试后比年轻女性表现出更大且持续的血压和血清HNE升高。同样，卵巢切除（OVX）大鼠的血清 NT 和血压（BP）显示出更大的增加。此外，在自发性高血压大鼠 (SHR) 中，跑步机运动可抑制高血压的发作，并增加血清和主动脉中的 NT 和 HNE。这些结果表明氧化应激参与绝经后心血管疾病和高血压的发病机制。在OVX大鼠中，内脏脂肪和胰岛素抵抗增加，而肠系膜内皮一氧化氮合酶（eNOS）表达减少。这些结果表明OVX大鼠提供了代谢综合征的模型。2)HNE对炎症发病机制的贡献LPS给药后，大鼠血清HNE因单核细胞NADPH氧化酶产生的超氧化物而短暂升高。在肠粘膜中，经过HNE修饰和聚合后，浆细胞在LPS后分泌IgA。此外，CYP和NADPH氧化酶在内质网中产生超氧化物和HNE，从而促进HNE修饰和GRP78.3)连接蛋白43 (Cx43)的有限蛋白水解在心肌细胞中上调，并导致缺血再灌注中的损伤和死亡。大鼠冠状动脉闭塞增加了Cx43表达和间隙连接细胞间通讯，从而促进收缩带坏死和梗塞发展的传播。在培养的心肌细胞中，缺血期间短暂的Cx43上调诱导Ca 2+ 通过半通道流入和细胞死亡。