The 4G/5G PAI-1 polymorphism influences the endothelial response to IL-1 and the modulatory effect of pravastatin

J Thromb Haemost. 2006 Aug;4(8):1798-803. doi: 10.1111/j.1538-7836.2006.02031.x.

Abstract

Background: Increased plasminogen activator inhibitor (PAI-1) levels lead to impaired fibrinolytic function associated with higher cardiovascular risk. PAI-1 expression may be regulated by different inflammatory cytokines such as interleukin-1alpha (IL-1). Several polymorphisms have been described in the PAI-1 gene.

Aim: We examined the influence of the 4G/5G polymorphism in the promoter region on IL-1alpha-induced PAI-1 expression by human umbilical vein endothelial cells (HUVEC) in presence or absence of pravastatin.

Methods and results: Genotyped HUVEC were incubated with IL-1alpha (500 U mL(-1)) in presence or absence of pravastatin (1-10 microm). PAI-1 expression was analyzed by real time polymerase chain reaction (PCR), and PAI-1 antigen measured in supernatants by ELISA. IL-1alpha increased PAI-1 secretion in a genotype-dependent manner, and higher values were observed for 4G/4G compared with both 4G/5G and 5G/5G cultures (P < 0.05). Preincubation of HUVEC with 10 microm pravastatin significantly reduced IL-1-induced PAI-1 expression in 4G/4G HUVEC compared with untreated cultures (177.5% +/- 24.5% vs. 257.9% +/- 39.0%, P < 0.05). Pravastatin also attenuated the amount of secreted PAI-1 by 4G/4G HUVEC after IL-1 stimulation (5020.6 +/- 165.7 ng mL(-1) vs. 4261.1 +/- 309.8 ng mL(-1), P < 0.05). This effect was prevented by coincubation with mevalonate, indicating a dependence on HMG-CoA reductase inhibition.

Conclusions: The endothelial 4G/5G PAI-1 genotype influences the PAI-1 response to IL-1alpha and the modulatory effect of pravastatin. As increased PAI-1 levels have been linked to cardiovascular disease the observed endothelial modulation by pravastatin may have potential clinical implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Atherosclerosis
  • Cells, Cultured
  • Endothelium, Vascular / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Genotype
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Interleukin-1 / metabolism*
  • Plasminogen Activator Inhibitor 1 / genetics*
  • Plasminogen Activator Inhibitor 1 / physiology*
  • Polymorphism, Genetic*
  • Pravastatin / pharmacology*
  • Promoter Regions, Genetic*
  • Umbilical Veins / cytology

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Interleukin-1
  • Plasminogen Activator Inhibitor 1
  • Pravastatin