Vascular biological analysis of risk factors for atherogenesis in diabetes - oxidative stress and hyperinsulinemia -

研究NIDDM患者中高血糖、氧化低密度脂蛋白和胰岛素抵抗等致动脉粥样硬化危险因素如何调节血管细胞功能是非常重要的。这些研究为糖尿病致动脉粥样硬化过程的新认识打开了一扇大门。我们已经报告了该领域的以下主题。1)高葡萄糖条件下的氧化应激;由于高葡萄糖条件下磷酸戊糖途径和谷胱甘肽氧化还原循环的活化受损，因此在高葡萄糖条件下清除氧自由基受损（Diabetologia，1994，Diabetes 1995，Diabetes 1996）。2)在高糖条件下，细胞表面ICAM-1的表达增加，导致单核细胞对内皮细胞的粘附增加（Life Science 1994）。3)糖尿病状态下氧化LDL的产生增加可刺激内皮细胞中单核细胞趋化蛋白-1（MCP-1）mRNA的表达。ox-LDL的活性成分之一 ...更多信息 是溶血磷脂酰胆碱（LPC），ox-LDL对MCP-1 mRNA表达的影响是通过细胞内自由基产生激活NF-κ B介导的（Mctabolism 1996，Diabetologia，出版中）。4)胰岛素抵抗与动脉粥样硬化细胞生长受胰岛素受体酪氨酸激酶和蛋白酪氨酸磷酸酶的调节。我们研究了非受体型PTP酶PTP 1B和SHP 2。高葡萄糖条件诱导的胰岛素信号传导受损由PTP 1B活化和酪氨酸磷酸化胰岛素受体去磷酸化介导（End J 1995，BBRC 1994）。此外，胰岛素增敏剂噻唑烷二酮衍生物改善了胰岛素信号传导中的这些异常（J Biol Chem 1995）。另一方面，在HIRc细胞中缺乏全长PTK结构域的突变型SHP 2的显性负表达诱导胰岛素信号传导受损（BBRC 1994，FEBS Lett 1994，J Biol Chem 1996，BBRC 1996）。5)高胰岛素血症、胰岛素抵抗和平滑肌细胞生长;生理浓度的胰岛素刺激培养的SMC中的PI 3-激酶和p70 S6 K活性。这些胰岛素作用因长期高胰岛素浓度而脱敏（Atherovirus 1995），氨基酸转运（A系统）因激活渥曼青霉素敏感性PI 3-激酶而刺激（Circ Res 1996）。少

It is very important to investigate how atherogenic risk factors such as hyperglycemia, oxidized LDL,and insulin resistance found in NIDDM patients modulate vascular cell function. These studies open a door for new insights of atherogenic process in diabetes. We have already reported the following topics in this field. 1) Oxidative stress in high glucose condition ; Scavenging of oxygen radicals was impaired in the high glucose condition because of impaired activation of pentose phosphate pathway and glutathione redox cycle in high glucose condition (Diabetologia, 1994, Diabetes 1995, Diabetes 1996). 2) In high glucose condition, expression of ICAM-1 was increased on cell surface in high glucose condition resulting in increased monocyte adhesiveness to endothelial cells (Life Science 1994). 3) Increased production of oxidized LDL in the diabetic condition could stimulate monocyte chemoattractant protein-1 (MCP-1) mRNA expression in endothelial cells. One of active components in ox-LDL … More was lysophosphatidylcholine (LPC) and ox-LDL effect on MCP-1 mRNA expression was mediated by activation of NF-kB through intracellular radical production (Mctabolism 1996, Diabetologia, in press). 4) Insulin resistance and atherosclerosis ; Cell growth is regulated by both insulin receptor tyrosine kinase and protein tyrosine phosphatases. We studied PTP1B and SHP2, non-receptor-type PTP ases. Impairment of Insulin signaling induced by high glucose condition was mediated by activation of PTP1B and dephosphorylation of tyr-phosphory-lated insulin receptors (End J 1995, BBRC 1994). Furthermore, insulin sensitizers, thiazolidine dione derivatives, improved these abnormalities in insulin signaling (J Biol Chem 1995). On the other hand, a dominant negative expression of mutant SHP2 lacking a full length PTPase domain in HIRc cells induced impairment of insulin signaling (BBRC 1994, FEBS Lett 1994, J Biol Chem 1996, BBRC 1996). 5) Hyperinsulinemia, insulin resistance and smooth muscle cell growth ; physiological concentrations of insulin stimulated PI3-kinase and p70S6K activities in cultured SMCs. These insulin action was desensitized by chronic high insulin concentrations (Atherosclerosis 1995) and an amino acid transport (A system) was stimulated by activation of Wortmannin-sensitive PI3-kinase (Circ Res 1996). Less