| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1996: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1995: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
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
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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
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