| Summary: | Increased plasma plasminogen activator inhibitor-1 (PAI-1) activity is a common finding in patients with coronary heart disease (CHD), particularly in young post-infarction patients with hypertriglyceridaemia, and is associated with recurrence of cardiovascular events. Both environmental and genetic factors contribute to determine plasma PAI-1 activity. A striking feature of PAI-1 is its positive association with the very low density lipoprotein (VLDL) triglycéride concentration. In the present study, we support the notion that a common 4G/5G polymorphic region in the PAI-1 promoter is involved in an allele-specific response to triglycérides. The slope of the regression line was steeper among individuals who were homozygous for the 4G allele as compared to individuals who were homozygous for the 5G allele. Transfection and DMA binding studies showed that the two proteins that previously been shown to bind to the 4G and 5G sequences (Eriksson et al. (1995) Proc. Natl. Acad. Sei. USA 92, 1851-1855), are not directly involved in an activation of the PAI-1 promoter mediated by VLDL. However, by transfection assay, VLDL was shown to induce transcription of the PAI-1 promoter in HUVEC:s. Maximum induction was obtained at 0.075 mg VLDL/ml culture medium. A promoter construct containing the 4G allele showed a slightly higher promoter activity in response to VLDL (3.8 fold induction) than did the promoter containing the 5G allele (2.3 fold induction). To localize the VLDL-response element, transfection studies with promoter deletions together with mobility shift assay and footprinting studies were performed. VLDL-induction of PAI-1 in endothelial cells was found to be caused by transcriptional activation mediated by a response element in the PAI-1 promoter located downstream and adjacent to the 4G/5G polymorphic site. Competitive binding of the factors binding to the polymorphic 4G/5G site and the VLDL induced factor could explain the allele specific response.
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