DIVERGENT EFFECTS OF TISSUE INHIBITOR OF METALLOPROTEINASE-1, METALLOPROTEINASE-2, OR METALLOPROTEINASE-3 OVEREXPRESSION ON RAT VASCULAR SMOOTH-MUSCLE CELL INVASION, PROLIFERATION, AND DEATH IN-VITRO - TIMP-3 PROMOTES APOPTOSIS

Tissue inhibitors of metalloproteinases (TIMPs) are a family of closel y related secreted proteins that limit matrix metalloproteinase (MMP) activity and also have direct effects on cell growth, We used the high ly efficient adenoviral delivery system to overexpress individual TIMP s from the cytomegalovirus immediate early promoter in rat aortic smoo th muscle cells, Overexpression of TIMP-1, -2, or -3, or a synthetic M MP inhibitor similarly inhibited SMC chemotaxis and invasion through r econstituted basement membrane, TIMP-1 overexpression did not effect c ell proliferation, By contrast, TIMP-2 caused a dose-dependent reducti on in proliferation, an effect not mimicked by a synthetic MMP inhibit or. TIMP-3 overexpression induced DNA synthesis, and promoted SMC deat h by apoptosis, a phenotype reproduced by adding TIMP-3 to uninfected cells, but not by a synthetic MMP inhibitor, Our study is the first to compare systematically the effect of overexpression of three TIMPs in any cell, We found similar effects on invasion mediated by inhibition of MMP activity, but widely divergent effects on proliferation and de ath through actions of TIMP-2 and -3 independent of MMP inhibition, Th ese findings have important implications for the physiological roles o f TIMPs and their use in gene therapy.