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Diabetes Publish Ahead of Print published online ahead of print January 26, 2007
DOI: 10.2337/db06-1199
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Original Research

Involvement of Heat Shock Factor-1 in Glycated Low Density Lipoprotein-Induced Upregulation of Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells

Ruozhi Zhao1, and Garry X. Shen1

1Departments of Internal Medicine and Physiology, University of Manitoba

Correspondence: gshen{at}ms.umanitoba.ca

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 low density lipoproteins (gly-LDL) stimulated the generation of PAI-1 from vascular endothelial cells (EC). The present study examined the effect of gly-LDL on the expression of heat shock factor-1 (HSF1), a physiological transcription factor of Hsp, and the involvement of HSF-1 in gly-LDL-induced production of PAI-1 in cultured human umbilical vein EC (HUVEC) and coronary artery EC (HCAEC). Treatment with gly-LDL increased the expression of HSF1 and Hsp-70 compared to LDL in subconfluent HCAEC or HUVEC, and that was associated with an increase of PAI-1 expression. The transfection of HSF1 gene enhanced the expression of PAI-1 in EC. Small interference RNA against HSF1 prevented gly-LDL-induced upregulation of PAI-1 in HCAEC or HUVEC. Gly-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 gly-LDL-induced increases of the expression of HSF1 or PAI-1 in EC. The results suggest that HSF-1 is involved in gly-LDL-induced upregulation of PAI-1 in subconfluent vascular EC through the binding of HSF1 to PAI-1 promoter. Glyco-oxidation may contribute to gly-LDL-induced expression of HSF1 and PAI-1 in EC.


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Copyright © 2007 by the American Diabetes Association.