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Effect of atorvastatin on plasminogen activator inhibitor type-1 synthesis in human monocytes/macrophages
S Lopez1, F Peiretti, B Bonardo
1Hematology Laboratory, Faculty of Medicine, Marseille, France.
Insights
Atorvastatin increases plasminogen activator inhibitor type 1 (PAI-1) synthesis in differentiating human monocytes but not in mature macrophages. This finding is crucial for understanding statin effects on atherothrombosis.
Area of Science:
- Cardiovascular Biology
- Cellular and Molecular Medicine
- Pharmacology
Background:
- Plasminogen activator inhibitor type 1 (PAI-1) is a key fibrinolytic inhibitor implicated in atherothrombosis.
- Macrophages infiltrating atherosclerotic lesions are a source of PAI-1.
- Statins are known to reduce atherosclerosis, prompting investigation into their molecular mechanisms.
Purpose of the Study:
- To investigate whether atorvastatin modulates the synthesis of PAI-1 in human monocytes and macrophages.
- To examine the effect of atorvastatin on PAI-1 production during different stages of monocyte/macrophage differentiation.
Main Methods:
- Studied atorvastatin's effect on PAI-1 synthesis in differentiated human promyelocytic cell line HL-60 and human peripheral blood monocyte-derived macrophages.
- Induced monocyte differentiation using phorbol myristate acetate (PMA) or transforming growth factor-beta type 1 (TGF-beta1)/1alpha,25-dihydroxyvitamin D3 (D3).
- Assessed PAI-1 and urokinase (uPA) synthesis under various conditions, including stimulation with tumor necrosis factor-alpha (TNF-alpha) and reversal with mevalonate.
Main Results:
- Atorvastatin significantly upregulated PAI-1 synthesis during early monocyte differentiation, particularly with TGF-beta1/D3 induction.
- Tumor necrosis factor-alpha (TNF-alpha) strongly induced PAI-1 synthesis, with atorvastatin showing a similar potentiating effect.
- Mevalonate reversed the PAI-1 enhancing effect of atorvastatin.
- In mature human monocyte-derived macrophages, atorvastatin had no significant effect on PAI-1 or uPA synthesis, irrespective of TNF-alpha, TGF-beta1, or PMA co-stimulation.
Conclusions:
- Atorvastatin upregulates PAI-1 synthesis during the early differentiation of monocytes into macrophages.
- Mature macrophages are not affected by atorvastatin regarding PAI-1 and uPA synthesis.
- These findings suggest a stage-specific effect of atorvastatin on PAI-1 production relevant to atherothrombosis research.
Abstract:
The fibrinolytic inhibitor plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of atherothrombosis and is produced by macrophages that infiltrate the atherosclerotic vessel wall. Because statins are effective in reducing atherosclerosis, we investigated if they modulate the synthesis of PAI-1 in human monocytes/macrophages. To this end, we studied the effect of atorvastatin in different models of monocyte/macrophage differentiation, such as differentiated human promyelocytic cell line HL-60 and human peripheral blood monocyte-derived macrophages. HL-60 cells were differentiated along monocyte lineage by phorbol myristate acetate (PMA) or a mixture of transforming growth factor-beta type 1 (TGF-beta1)/1alpha,25-dihydroxyvitamin D3 (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 of the same order as in the absence of TNF-alpha. Mevalonate reversed the enhancing effect of atorvastatin. In mature human monocyte-derived macrophages, 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 very low in human monocyte-derived macrophages, was not altered by atorvastatin. 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. Atorvastatin did not significantly interact with the upregulating action of TNF-alpha on PAI-1 synthesis during differentiation.