UP-REGULATION OF PAI-1 SYNTHESIS BY INSULIN AND PROINSULIN IN HEP G2 CELLS BUT NOT IN ENDOTHELIAL-CELLS

Increased plasminogen activator inhibitor 1 (PAI-1) plasma levels have been described in patients with ischemic heart disease, Although the regulation of PAI-1 production is still not completely understood, the important role of metabolic factors has been suggested. Clinical and biochemical changes found in the 'syndrome X' are significantly correl ated to plasma PAI-1 level, Intact proinsulin and its derivates have b een observed in plasma and shown to possess immunological reactivity s imilar to that of insulin in conventional radioimmunoassay, PAI activi ty has been shown in diabetic patients to better correlate with plasma levels of proinsulin and split products than with insulin, These data question the existing relationship between insulin, proinsulin, and c ellular PAI-1 production, We have compared the effect of insulin and p roinsulin on PAI-1 synthesis by Hep G2 cells, and endothelial cells fr om human umbilical vein and porcine aorta, Our results indicated that proinsulin and insulin increased PAI-1 synthesis by Hep G2 cells, Neve rtheless the proinsulin-induced up-regulation always represented 2 to 4% of the insulin's effect, on a molar basis, Conversely to previous r eports we cannot demonstrate an effect of proinsulin or insulin on PAI -1 synthesis by endothelial cells irrespective of their origin, Theref ore, in so far as in vitro results can be extrapolated to the in vivo situation in insulin resistant patients, and in so far as insulin and precursors play a role in PAI-1 synthesis regulation in these patients , elevated PAI-1 levels observed in insulin resistant and/or coronary heart disease patients might be the result of increased synthesis of P AI-1 localized at the hepatocyte level.