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Involvement of Heat Shock Factor-1 in Glycated LDL–Induced Upregulation of Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells

From the Departments of Internal Medicine and Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

Address correspondence and reprint requests to Garry X. Shen, MD, PhD, Diabetes Research Group, University of Manitoba, 835-715 McDermot Ave., Winnipeg, Manitoba, Canada R3E 3P4. E-mail: gshen{at}ms.umanitoba.ca

Abbreviations: BHT, butylated hydroxytoluene; BHT-gLDL, LDL glycated with the presence of 80 µmol/l BHT; CAD, coronary artery disease; EMSA, electrophoretic mobility shift assay; HCAEC, human coronary artery endothelial cell; HSE, heat shock responsive element; HSF1, heat shock factor-1; Hsp, heat shock protein; HUVEC, human umbilical vein endothelial cell; PAI-1, plasminogen activator inhibitor-1; ROS, reactive oxygen species; siRNA, small interference RNA; SOD, superoxide dismutase

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.

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