PLASMINOGEN-ACTIVATOR INHIBITOR-1 IS AN IMMEDIATE-EARLY RESPONSE GENEIN REGENERATING RAT-LIVER

Plasminogen activator inhibitor-1 (PAI-1), a M(r) 50,000 serine protea se inhibitor, is the major physiological inhibitor of plasminogen acti vation. Quiescent rat hepatocytes do not express the PAI-1 gene in viv o; however, PAI-1 is synthesized both by primary cultures of rat hepat ocytes and by hepatoma cells in vitro. Furthermore, PAI-1 is expressed by fibroblastic cells in vitro, in response to mitogen stimulation, s uggesting a possible connection between hepatocyte PAI-1 expression an d cell proliferation. To determine whether PAI-1 is an early growth re sponse gene in hepatocytes in vivo, we analyzed its expression in rege nerating rat liver Male rats underwent partial (70%) hepatectomy (PR) or sham operation (SO), and liver samples were analyzed by Northern bl ot analysis and in situ hybridization. PAI-1 mRNA was not present at t ime 0 h, nor at any other time in SO rats but was induced rapidly in r egenerating livers, peaking at 2 h and declining to negligible levels by 8 h posthepatectomy. This induction was not inhibited by cyclohexim ide. In situ hybridization analysis localized PAI-1 transcripts to hep atocytes. Immunohistochemical analysis demonstrated PAI-1-specific sta ining in hepatocytes in the livers of both PR and SO rats, but the tem poral and spatial distribution profiles differed between PH and SO rat s. Our studies demonstrate that PAI-1 is an immediate early response g ene, transiently expressed in regenerating liver, expression of which may be important in hepatocyte growth and proliferation in vivo.