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.
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.
Eriksson
P
P
King Gustaf V Research Institute, Department of Medicine, Karolinska Hospital, Stockholm, Sweden. perikson@instmed.ks.se
Nilsson
L
L
Karpe
F
F
Hamsten
A
A
D001483:Base Sequence; D001667:Binding, Competitive; D002478:Cells, Cultured; D018983:DNA Footprinting; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005342:Fibrinolysis / Q000235:genetics; D006801:Humans; D015228:Hypertriglyceridemia / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000494:pharmacology*; D008969:Molecular Sequence Data; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
D008079:Lipoproteins, VLDL; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D014157:Transcription Factors