| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2001: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2000: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
The aim of this experiment was to examine the characterization of platelet-derived growth factor (PDGF)-induced p38 mitogen-activated protein kinase (p38) activation and its biological effects in the diabetic vascular smooth muscle cells (VSMCs). PDGF-BB activated p38 phosphorylation dose-dependently, and the level was more drastic in diabetic cells. These phosphorylations were specifically inhibited by SB-203580, a specific inhibitor of p38, but not by PD-98059. However, PDGF-BB did not affect the protein level of p38. PDGF-BB also activated the translocation of protein kinase C (PKC) - δ and the phosphorylation of MKK 3 / MKK 6 but not that of either stress-activated protein kinase. In the upstream level, PDGF-induced p38 activation was regulated the Rho A, one of the members of small G proteins. The amounts of DNA synthesis and migration stimulated by PDGF-BB were prevented by SB-203580 dose-dependently. Althou the detection of apoptotic cells was evaluated by the TUNEL method, PDGF-BB-stimulated VSMCs did not show apoptotic change in spite of the presence or absence of SB-203580. In addition, the stimulation of PDGF-BB enhanced the levels of arachidonic release and COX-2, and these levels were more increased in VSMCs from diabetic rats. These values were also decreased by SB-203580. These results established that PDGF-BB activated p38 and subsequently regulated cell growth in VSMCs, providing a molecular mechanism by which p38 MAP kinase can cause the development of cardiovascular diseases, including atherosclerosis. Furthermore, this activation was more enhanced in diabetes.
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