The synthetic metalloproteinase inhibitor batimastat suppresses injury-induced phosphorylation of MAP kinase ERK1/ERK2 and phenotypic modification of arterial smooth muscle cells in vitro.
Smooth muscle cell (SMC) migration and proliferation are important events in the formation of intimal lesions associated with atherosclerosis and restenosis following balloon angioplasty. The extracellular matrix has important functions in modulating SMC structure and function, but less is known about the role of the matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors. The present study investigates the effects of the synthetic MMP inhibitor batimastat (BB94) on vascular SMCs. As experimental model, rat aortic smooth muscle cells in primary and secondary cultures were employed. 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 moving into an injured zone. Gelatin zymography was used for the detection of 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 blotting. The results show that BB94 restrained the phenotypic modulation of vascular SMCs in primary cultures and suppressed injury-induced DNA synthesis and migration. Moreover, the upregulation of ERK1/ERK2 phosphorylation in injured secondary cultures and in cells treated with bFGF was markedly reduced by BB94, whereas TIMP-2 lacked a clear effect. Our data suggest that BB94 inhibits injury-induced activation of vascular SMCs by acting on MMPs as well as other targets.
Lövdahl
C
C
Department of Cell and Molecular Biology, Section for Connective Tissue Biology, Lund University, Lund, Sweden. cecilia.lovdahl@medkem.lu.se
Thyberg
J
J
Hultgârdh-Nilsson
A
A
D000818:Animals; D001158:Arteries; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005780:Gelatin / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008854:Microscopy, Electron; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000648:ultrastructure; D010641:Phenotype; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; D005780:Gelatin; C080985:batimastat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008666:Metalloendopeptidases