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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.

Journal of Cardiovascular Pharmacology
|June 8, 2001
PubMed

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.

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