Daum G, Levkau B, Chamberlain N L, Wang Y, Clowes A W
Department of Surgery, University of Washington, Seattle 98195, USA.
Mol Cell Biochem. 1998 Jun;183(1-2):97-103. doi: 10.1023/a:1006820214072.
Vanadate has been considered in the treatment of diabetes because of its insulin-like effects. However, it has severe toxic effects in both animal and man. In cultured cells, vanadate can either cause death or be growth stimulatory, depending on the cell type and growth conditions. Here, we report that in baboon aortic smooth muscle cells (SMCs), vanadate induced p42/p44 mitogen-activated protein kinase (MAPK) activity. This effect was abolished in the presence of the specific MAPK kinase (MAPKK) inhibitor PD098059. Although activation of p42/p44MAPK/MAPKK is generally thought to be necessary for proliferation, in SMCs, vanadate did not promote DNA synthesis and inhibited thymidine incorporation stimulated by platelet-derived growth factor (PDGF)-BB in a dose dependent fashion (IC50: 30 microM). Prolonged exposure to vanadate exerted cytotoxic effects. Cells retracted, rounded up and detached from the substratum. These vanadate-induced morphological changes were blocked in the presence of PD098059. The addition of PDGF-BB further activated p42/p44MAPK/MAPKK in the presence of vanadate and substantially increased vanadate toxicity. We conclude from these observations that activation of the p42/p44MAPK/MAPKK signalling module contributes to the cytotoxic effects induced by vanadate.
由于钒酸盐具有类胰岛素作用，因此一直被用于糖尿病治疗。然而，它在动物和人类中均具有严重的毒性作用。在培养细胞中，钒酸盐可导致细胞死亡或具有生长刺激作用，这取决于细胞类型和生长条件。在此，我们报道在狒狒主动脉平滑肌细胞（SMC）中，钒酸盐可诱导p42/p44丝裂原活化蛋白激酶（MAPK）活性。在存在特异性MAPK激酶（MAPKK）抑制剂PD098059的情况下，这种作用被消除。尽管通常认为p42/p44MAPK/MAPKK的激活对于增殖是必需的，但在SMC中，钒酸盐并未促进DNA合成，而是以剂量依赖方式（IC50：30 microM）抑制血小板衍生生长因子（PDGF）-BB刺激的胸苷掺入。长时间暴露于钒酸盐会产生细胞毒性作用。细胞收缩、变圆并从基质上脱离。在存在PD098059的情况下，这些钒酸盐诱导的形态学变化被阻断。在存在钒酸盐的情况下，添加PDGF-BB可进一步激活p42/p44MAPK/MAPKK，并显著增加钒酸盐的毒性。我们从这些观察结果得出结论，p42/p44MAPK/MAPKK信号模块的激活有助于钒酸盐诱导的细胞毒性作用。
