Redox-regulation by active oxygen species / nitric oxide in cardiovascular system

目的1)证明冠状动脉内皮细胞和平滑肌细胞和心肌细胞产生的活性氧/一氧化氮是氧化还原调节的启动物。2)从氧化还原调节角度探讨脂蛋白（LDL、HDL、TG）对内皮细胞PAI-1分泌的影响。3)采用小鼠动脉粥样硬化模型，探讨氧化还原调控在不稳定动脉粥样硬化形成中的作用。结果1)利用电子自旋共振（ESR）、化学发光和荧光等方法研究了不同细胞产生活性氧和一氧化氮的初始氧化还原调控。2)在脂蛋白存在下，内皮细胞分泌PAI-1。HDL组PAI-1的分泌量大于LDL组。这些结果与目前关于HDL抗动脉粥样硬化作用的认识不一致。因此，我们认为动脉粥样硬化患者PAI-1升高不是原因，而是结果。3) ApoE^<-/->/iNOS^<-/->和ApoE^<-/->/iNOS^<+/+>小鼠的动脉粥样硬化大小相当。两者的重要区别是ApoE^<-/->/iNOS^<+/+>小鼠的动脉粥样硬化是不稳定的；少胶原蛋白和富含脂质。在ApoE^<-/->/iNOS^<+/+>小鼠中，基质金属蛋白酶（Matrix metalloproteinase， MMP）可能通过诱导iNOS被氧化还原调控机制激活。结论氧化还原酶介导的调控在心血管发病中起重要作用。

Purposes1) To demonstrate active oxygen species/nitric oxide generation from endotherial and smooth muscle cells of coronary artery and cardiac myocytes as initiators of redox-regulation.2) To examine effects of lipoproteins (LDL, HDL, and TG) on PAI-1 secreation endotherial cells from the aspect of redox-regulation.3) To examine redox-regulation in the formation of unstable atheroma using mice atheroma model.Results1) The generation of active oxygen species and nitric oxide from various cells was shown to initial redox-regulation by using electron spin resonance (ESR), chemiluminescence and fluorescence methods.2) In the presence of lipoproteins endotherial cells secreated PAI-1. The amount of PAI-1 secreation was greater in HDL than in LDL additions. These results do not agree with the present knowledge of anti-atherogenic role of HDL. Thus we suggest that the increased PAI-1 in patient with atherosclerosis is not the cause but the consequence.3) Both ApoE^<-/->/iNOS^<-/-> and ApoE^<-/->/iNOS^<+/+> mice fed with atherogenic diet developed comparable size of atheroma. The important difference between the two was atheroma in ApoE^<-/->/iNOS^<+/+> mice was unstable ; less collagen and lipid-rich. Matrix metalloproteinase (MMP) was activated by possibly redox-regulated mechanism though induction of iNOS in ApoE^<-/->/iNOS^<+/+> mice.ConclusionRedox-mediated regulation appears to play an important role on cardiovascular pathogenesis.