Expression of plasminogen activator inhibitor-1 in human adipose tissue: arole for TNF-alpha?

Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsib le for reduced fibrinolysis, are associated with animal and human obesity a nd with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms r egulating such an expression remain to be elucidated. In omental and/or sub cutaneous biopsies from obese non-diabetic patients, incubated in Medium 19 9, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly e vident also in collagenase isolated human adipocytes and that it is stimula ted by incubation itself and enhanced by exogenous human tumor necrosis fac tor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biop sies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maxim al inhibitory effect at 10(-3) M, the same inhibitory effect caused by Geni stein at 100 mu g/ml. This was associated to a marked inhibition of PAI-1 m RNA and of endogenous TNF-alpha production. Furthermore, when human fat bio psies were incubated in the presence of polyclonal rabbit neutralizing anti -human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml hum an TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8 +/- 19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that P AI-1 expression is present in human isolated adipocytes and that it is enha nced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore o ur data support the possibility of a main role of endogenous TNF-alpha on h uman adipose tissue PAI-1 expression. This cytokine, produced by human adip ose tissue and causing insulin resistance, may be a link in the clinical re lationship between insulin-resistance syndrome and increased PAI-1 plasma l evels. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.