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

1)4-羟基壬烯醛(HNE)和硝基酪氨酸(NT)在生活方式疾病发病机制中的作用绝经后妇女经心理应激色词测验后，血压和血清HNE较青年妇女有较大幅度和持续性的升高。同样，去卵巢(OVX)大鼠的血清NT和血压(BP)也有较大幅度的升高。此外，在自发性高血压大鼠(SHR)中，跑台运动抑制了高血压的发生，并抑制了血清和主动脉中NT和HNE的增加。这些结果表明氧化应激参与了绝经后心血管疾病和高血压的发病。去卵巢大鼠肠系膜内脏脂肪增加，胰岛素抵抗增加，内皮型一氧化氮合酶(ENOS)表达减少。这些结果提示OVX大鼠提供了一种代谢综合征的模型。2)HNE在炎症发病机制中的作用内毒素注射后，大鼠血清HNE由单核细胞NADPH氧化酶产生的超氧化物短暂升高。在肠粘膜，经HNE修饰和聚合后，浆细胞可分泌出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的修饰和GRP78.3)连接蛋白43(Cx43)上调心肌细胞的连接蛋白43，从而导致缺血再灌注损伤和死亡。大鼠冠状动脉闭塞后，Cx43表达增加，缝隙连接细胞间通讯增加，从而促进收缩带坏死的传播和脑梗塞的发展。在培养的心肌细胞中，缺血时Cx43的瞬时上调导致钙离子通过半通道内流和细胞死亡。

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.