THE MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY CONTRIBUTES TO VANADATE TOXICITY IN VASCULAR SMOOTH-MUSCLE CELLS

Vanadate has been considered in the treatment of diabetes because of i ts 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 condition s. Here, we report that in baboon aortic smooth muscle cells (SMCs), v anadate induced p42/p44 mitogen-activated protein kinase (MAPK) activi ty. This effect was abolished in the presence of the specific MAPK kin ase (MAPKK) inhibitor PD098059. Although activation of p42/p44(MAPK)/M APKK is generally thought to be necessary for proliferation, in SMCs, vanadate did not promote DNA synthesis and inhibited thymidine incorpo ration stimulated by platelet-derived growth factor (PDGF)-BB in a dos e dependent fashion (IC50: 30 mu M). Prolonged exposure to vanadate ex erted cytotoxic effects. Cells retracted, rounded up and detached from the substratum. These vanadate-induced morphological changes were blo cked in the presence of PD098059. The addition of PDGF-BB further acti vated p42/ p44(MAPK)/MAPKK in the presence of vanadate and substantial ly increased vanadate toxicity. We conclude from these observations th at activation of the p42/p44(MAPK)/MAPKK signalling module contributes to the cytotoxic effects induced by vanadate.