Involvement of heat shock factor-1 in glycated LDL-induced upregulation of plasminogen activator inhibitor-1 in vascular endothelial cells.
Coronary artery disease is the predominant cause of death in diabetic patients. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of plasminogen activators. Heat shock protein (Hsp) was upregulated in uncontrolled diabetic patients. Our previous studies demonstrated that glycated LDL stimulated the generation of PAI-1 from vascular endothelial cells. The present study examined the effect of glycated LDL on the expression of heat shock factor-1 (HSF1), a physiological transcription factor of Hsp, and the involvement of HSF-1 in glycated LDL-induced production of PAI-1 in cultured human umbilical vein endothelial cells (HUVECs) and coronary artery endothelial cells (HCAECs). Treatment with glycated LDL increased the expression of HSF1 and Hsp-70 compared with LDL in subconfluent HCAECs or HUVECs, and that was associated with an increase of PAI-1 expression. The transfection of HSF1 gene enhanced the expression of PAI-1 in endothelial cells. Small interference RNA against HSF1 prevented glycated LDL-induced upregulation of PAI-1 in HCAECs or HUVECs. Glycated LDL increased the binding of a nuclear protein to the PAI-1 promoter. The nuclear protein-DNA complex was supershifted by HSF1 antibody. The presence of an antioxidant, butylated hydroxytulene, during the glycation of LDL prevented glycated LDL-induced increases of the expression of HSF1 or PAI-1 in endothelial cells. The results suggest that HSF-1 is involved in glycated LDL-induced upregulation of PAI-1 in subconfluent vascular endothelial cells through the binding of HSF1 to PAI-1 promoter. Glyco-oxidation may contribute to glycated LDL-induced expression of HSF1 and PAI-1 in endothelial cells.
Zhao
Ruozhi
R
Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
Shen
Garry X
GX
D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006031:Glycosylation; D006360:Heat-Shock Proteins / Q000494:pharmacology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014162:Transfection; D014471:Umbilical Veins
D006360:Heat-Shock Proteins; D008077:Lipoproteins, LDL; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human