The synthetic metalloproteinase inhibitor batimastat suppresses injury-induced phosphorylation of MAP kinase ERK1/ERK2 and phenotypic modification ofarterial smooth muscle cells in vitro

Smooth muscle cell (SMC) migration and proliferation are important events i n the formation of intimal lesions associated with atherosclerosis and rest enosis following balloon angioplasty. The extracellular matrix has importan t functions in modulating SMC structure and function, but less is known abo ut the role of the matrix metalloproteinases (MMPs) and their endogenous ti ssue inhibitors. The present study investigates the effects of the syntheti c MMP inhibitor batimastat (BB94) on vascular SMCs. As experimental model, rat aortic smooth muscle cells in primary and secondary cultures were emplo yed. Electron microscopy was used to investigate the effects of BB94 on the overall phenotypic properties of the cells. Induction of DNA synthesis and migration was studied by thymidine autoradiography and counting of cells m oving into an injured zone. Gelatin zymography was used for the detection o f BB94-mediated inhibition of injury-induced MMP activity. Phosphorylation of the mitogen-activated protein kinases ERK1/ERK2, two potential mediators of the injury-induced activation of the cells, was measured by Western blo tting. The results show that BB94 restrained the phenotypic modulation of v ascular SMCs in primary cultures and suppressed injury-induced DNA synthesi s and migration. Moreover, the upregulation of ERK1/ERK2 phosphorylation in injured secondary cultures and in cells treated with bFGF was markedly red uced by BB94, whereas TIMP-2 lacked a clear effect. Our data suggest that B B94 inhibits injury-induced activation of vascular SMCs by acting on MMPs a s well as other targets. Copyright (C) 2000 S. Karger AG. Basel.