INVOLVEMENT OF U-PA IN THE ANTI-APOPTOTIC ACTIVITY OF TGF-BETA FOR VASCULAR SMOOTH-MUSCLE CELLS

Previous studies suggest a role for the plasminogen or fibrinolytic sy stem in the activation of latent-transforming growth beta (L-TGF beta) into active TGF beta. Zn the present study, the anti-apoptotic activi ty of TGF beta on cultured vascular smooth muscle cells (SMC) isolated from the aorta of transgenic mice with single inactivation of genes e ncoding the tissue-type plasminogen activator (t-PA(-/-)), urokinase-t ype plasminogen activator (u-PA(-/-)), urokinase receptor (u-PAR(-/-)) or plasminogen (Plg(-/-)) genes was examined. Latent-TGF beta inhibit ed serum deprivation-induced apoptosis of SMC isolated from wildtype a nd t-PA(-/-) mice but failed to reduce apoptosis of SMC isolated from u-PA(-/-), u-PAR(-/-) or Plg(-/-) mice. Active TGF beta, however, was able to inhibit serum deprivation-induced apoptosis of these 5 cell ty pes, indicating that u-PA and/or plasmin were in involved in the activ ation of L-TGF beta, The antiapoptotic effect of L-TGF beta could not be evoked by addition of exogenous t-PA to u-PA(-/-) cells, but,vas re vealed by addition of exogenous u-PA or plasmin, This effect was depen dent on the catalytic activity of plasmin as revealed by the dose-depe ndent inhibition of aprotinin or epsilon aminocaproic acid (EACA), The se results therefore indicate that, at least in vitro, u-PA-mediated p lasmin, through the generation of active TGF beta from L-TGF beta, is required for the anti-apoptotic activity of TGF beta on SMC. (C) 1997 Federation of European Biochemical Societies.