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Characterization of Platelet-Derived Growth Factor-Induced p38 Mitogen-Activated Protein Kinase Activation and its Biological Effects in the Diabetic Vascular Wall Cells

血小板衍生生长因子诱导的 p38 丝裂原激活蛋白激酶激活的表征及其在糖尿病血管壁细胞中的生物学效应

基本信息

批准号：
12671097
负责人：
IGARASHI Masahiko
金额：
$ 2.3万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671097/
关键词：
p38 PDGF-BB Vascular Smooth Muscle Cell Diabetes COX-2 Inflammation PKC Small G Protein ラットコラーゲン ROCK アンチセンス SB-203580 PPAR-γ

项目摘要

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.

本实验的目的是检查血小板衍生生长因子 (PDGF) 诱导的 p38 丝裂原激活蛋白激酶 (p38) 激活的特征及其在糖尿病血管平滑肌细胞 (VSMC) 中的生物学效应。 PDGF-BB 剂量依赖性地激活 p38 磷酸化，并且在糖尿病细胞中该水平更为剧烈。这些磷酸化可被 p38 的特异性抑制剂 SB-203580 特异性抑制，但不能被 PD-98059 抑制。然而，PDGF-BB不影响p38的蛋白水平。 PDGF-BB 还激活蛋白激酶 C (PKC) - δ 的易位和 MKK 3 / MKK 6 的磷酸化，但不激活任一应激激活蛋白激酶的磷酸化。在上游水平，PDGF 诱导的 p38 激活受到小 G 蛋白成员之一的 Rho A 的调节。 SB-203580 剂量依赖性地阻止 PDGF-BB 刺激的 DNA 合成和迁移量。尽管通过TUNEL方法评估了凋亡细胞的检测，但无论SB-203580存在或不存在，PDGF-BB刺激的VSMC均未显示凋亡变化。此外，PDGF-BB的刺激增强了花生四烯酸的释放和COX-2的水平，并且这些水平在糖尿病大鼠的VSMC中增加得更多。 SB-203580 也降低了这些值。这些结果表明，PDGF-BB 激活 p38，随后调节 VSMC 中的细胞生长，从而提供了 p38 MAP 激酶导致包括动脉粥样硬化在内的心血管疾病发生的分子机制。此外，这种激活在糖尿病中更加增强。