Effect of atorvastatin on plasminogen activator inhibitor type-1 synthesisin human monocytes/macrophages

The fibrinolytic inhibitor plasminogen activator inhibitor type 1 (PAI-1) p lays a role in the development of atherothrombosis and is produced by macro phages that infiltrate the atherosclerotic vessel wall. Because statins are effective in reducing atherosclerosis, we investigated if they modulate th e synthesis of PAI-1 in human monocytes/macrophages. To this end, we studie d the effect of atorvastatin in different models of monocyte/macrophage dif ferentiation, such as differentiated human promyelocytic cell line HL-60 an d human peripheral blood monocyte-derived macrophages. HL-60 cells were dif ferentiated along monocyte lineage by phorbol myristate acetate (PMA) or a mixture of transforming growth factor-beta type 1 (TGF-beta1)/1 alpha ,25-d ihydroxyvitamin D-3 (D3). In these conditions, PAI-1 synthesis was strongly induced and atorvastatin upregulated this synthesis, especially during TGF -beta1/D3-induced differentiation. Recombinant human tumor necrosis factor- alpha (TNF-alpha) strongly upregulated PAI-1 synthesis in PMA- or TGF-beta1 /D3-differentiated cells, and the potentiating effect of atorvastatin was o f the same order as in the absence of TNF-alpha. Mevalonate reversed the en hancing effect of atorvastatin. In mature human monocyte-derived macrophage s, atorvastatin, alone or in combination with TNF-alpha, TGF-beta1, or PMA, did not exert any significant effect on PAI-1 synthesis. Basal production of urokinase (uPA), which was below detection limits in HL-60 cells and ver y low in human monocyte-derived macrophages, was not altered by atorvastati n. These results show that atorvastatin upregulates PAI-1 synthesis during the early stages of monocyte/macrophage differentiation, but has no effect on PAI-1 and uPA synthesis in mature human monocyte-derived macrophages. At orvastatin did not significantly interact with the upregulating action of T NF-alpha on PAI-1 synthesis during differentiation.