Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia.
Eriksson P., Nilsson L., Karpe F., Hamsten A.
Hypertriglyceridemia and impaired fibrinolytic function are linked to coronary heart disease and other atherothrombotic disorders. Triglyceride-rich lipoproteins may attenuate fibrinolysis by increasing the plasma levels of plasminogen activator inhibitor-1 (PAI-1). Furthermore, a common 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene has been indicated to influence plasma PAI-1 activity and to be involved in an allele-specific response to triglycerides. Herein we show by transfection assays that VLDLs induce transcription of the human PAI-1 promoter in endothelial cells. A VLDL response element (VLDLRE) is located to residues -672 to -657 in the promoter region by electromobility shift assay, methylation interference, and DNase I footprinting, and its activity is shown to be influenced by the common 4G/5G polymorphism located adjacent to and upstream of the binding site of a VLDL-inducible transcription factor. These findings may provide a molecular explanation to the link between VLDL and PAI-1 activity elevation in plasma and to the interaction between the 4G/5G polymorphism and plasma triglycerides.