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

糖尿病动脉粥样硬化危险因素的血管生物学分析 - 氧化应激和高胰岛素血症 -

• 批准号: 07671127
• 负责人: KASHIWAGI Atsunori
• 金额: $ 1.47万
• 依托单位: Shiga University of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671127/
• 关键词: Diabetes mellitus; Risk factors for atherogenesis; Vascular biology; Oxidative stress; Hyperinsulinemia; Lysophosphatidylcholine; MCP-1; Vascular endothelial cells

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

研究 NIDDM 患者中发现的高血糖、氧化 LDL 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非常重要。这些研究为糖尿病动脉粥样硬化过程的新见解打开了大门。我们已经报道了该领域的以下主题。 1）高糖条件下的氧化应激；由于高葡萄糖条件下戊糖磷酸途径和谷胱甘肽氧化还原循环的激活受损，氧自由基的清除在高葡萄糖条件下受损（Diabetologia，1994，Diabetes 1995，Diabetes 1996）。 2)在高糖条件下，细胞表面ICAM-1的表达增加，导致单核细胞与内皮细胞的粘附性增加(Life Science 1994)。 3) 糖尿病状态下氧化低密度脂蛋白的产生增加可以刺激内皮细胞中单核细胞趋化蛋白-1 (MCP-1) mRNA 的表达。 ox-LDL 中的活性成分之一是溶血磷脂酰胆碱 (LPC)，ox-LDL 对 MCP-1 mRNA 表达的影响是通过细胞内自由基生成激活 NF-kB 介导的（Mctabolism 1996，Diabetologia，出版中）。 4）胰岛素抵抗和动脉粥样硬化；细胞生长受到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 PTP1B 和 SHP2，即非受体型 PTP 酶。高葡萄糖条件诱导的胰岛素信号传导受损是通过 PTP1B 的激活和酪氨酸磷酸化胰岛素受体的去磷酸化介导的（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的这些异常（J Biol Chem 1995）。另一方面，HIRc 细胞中缺乏全长 PTPase 结构域的突变体 SHP2 的显性负表达会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 PI3 激酶和 p70S6K 活性。这些胰岛素作用因长期高胰岛素浓度而变得不敏感（动脉粥样硬化，1995），并且通过激活渥曼青霉素敏感的PI3激酶（Circ Res 1996）刺激氨基酸转运（A系统）。较少的

项目成果

Taki H, et al.: "Expression of intercellular adhesion molecules 1 (ICAM-1) via an osmotic effect in human umbilical vein endotheliad cells exposed to high glucose medium." Life Science. 58. 1713-1721 (1996)

Taki H 等人：“暴露于高葡萄糖培养基的人脐静脉内皮细胞通过渗透效应表达细胞间粘附分子 1 (ICAM-1)。”

Maegawa H, et al.: "SHPTP2 serves adapter protein linking between Janus kinase 2 and insulin receptor substrates." Biochem Biophys Res Commun. 228. 122-127 (1996)

Maekawa H 等人：“SHPTP2 充当连接 Janus 激酶 2 和胰岛素受体底物之间的衔接蛋白。”

Takahara N, et al.: "Oxidaized lipoproteins found in patients with non-insulin-dependent diabetes mallitus stimulate radical-induced MCP-1 mRNA expression in cultured human endothelial cells." Diabetologia. (in press).

Takahara N 等人：“在非胰岛素依赖型糖尿病患者中发现的氧化脂蛋白会刺激培养的人内皮细胞中自由基诱导的 MCP-1 mRNA 表达。”

2.Ugi,S.,et al.: "Src homology 2 domains of protein tyrosine phosphatase are associated in vitro with both the insulin receptor and insulin receptor substrate-1 via different phosphotyrosine motifs." FEBS Lett. 340. 216-220 (1994)

2.Ugi,S.,et al.：“蛋白酪氨酸磷酸酶的 Src 同源 2 结构域在体外通过不同的磷酸酪氨酸基序与胰岛素受体和胰岛素受体底物 1 相关。”

8.Takagi Y,et al.: "Significance of fructose-induced protein oxidation and formation of advanced glycation end product." J.Diab Compl. 9. 87-91 (1995)

8.Takagi Y 等人：“果糖诱导的蛋白质氧化和晚期糖基化终产物形成的意义。”