SENESCENCE-DEPENDENT REGULATION OF TYPE-1 PLASMINOGEN-ACTIVATOR INHIBITOR IN HUMAN VASCULAR ENDOTHELIAL-CELLS

Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibito r plasminogen activator and has been found to be increased in a number of clinical conditions generally defined as prothrombotic. Since in a ging and in atherosclerosis the changes observed in the endothelium re semble those of in vitro aged endothelial cells, we have examined the expression of PAI-1 in cells at different population doublings. In sen escent endothelial cells, PAI-1 mRNA and protein are constitutively hi gh, but uninducible by exogenous interleukin 1 alpha as well as by the phorbol ester TPA. Interestingly the increase of PAI-1 levels correla tes with the upregulation of interleukin 1 alpha, which characterizes endothelial cell senescence. Since PAI-1 expression is not increased i n young cells made nondividing by contact inhibition, we anticipate th at PAI-1 expression can be used as an appropriate marker of endothelia l senescence. Moreover, PAI-1 was not upregulated in senescent or in p rogeric human fibroblasts, which do not overexpress interleukin 1 a, t hus suggesting that multiple pathways may exist to regulate aging of h uman fibroblasts and endothelial cells. (C) 1995 Academic Press, Inc.