Transcriptional regulation of plasminogen activator inhibitor-1 in vascular endothelial cells induced by oxidized very low density lipoproteins.
Elevated levels of triglycerides and very low density lipoproteins (VLDL) are biochemical markers of metabolic syndrome and diabetes. VLDL from hypertriglyceridemic or diabetic patients increased the generation of plasminogen activator inhibitor-1 (PAI-1) from cultured vascular endothelial cells (EC). Susceptibility of VLDL to peroxidation was increased in diabetic patients. Heat shock factor-1 (HSF1) is implicated in the transcriptional regulation of PAI-1 induced by glycated low density lipoprotein (LDL). The present study examined the effects of oxidized VLDL (oxVLDL) on the expression of PAI-1 and HSF1 in cultured human EC and mouse embryo fibroblasts (MEF). OxVLDL modified by copper or iron ions increased the expression of PAI-1 and HSF1 in EC compared to VLDL or LDL. Butylated hydroxytulene inhibited oxVLDL-induced expression of PAI-1 and HSF1 in EC. OxVLDL increased the binding of HSF1 to PAI-1 promoter. Short interference RNA for HSF1 inhibited oxVLDL-induced PAI-1 expression in EC. OxVLDL stimulated the expression of PAI-1 from MEF of wild-type mice, but failed to increase PAI-1 expression in MEF of HSF1-knockout mice. The results indicate that oxVLDL increased PAI-1 expression, and HSF1 mediates the transcription of PAI-1 in cultured vascular EC or fibroblasts.
Zhao
Ruozhi
R
Departments of Internal Medicine and Physiology, University of Manitoba, Winnipeg, Manitoba, Canada, R3E 3P4.
Ma
Xiuli
X
Shen
Garry X
GX
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D000076249:Heat Shock Transcription Factors; D006801:Humans; D008079:Lipoproteins, VLDL / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D000975:Antioxidants; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D008079:Lipoproteins, VLDL; D017395:Plasminogen Activator Inhibitor 1; D014157:Transcription Factors; C108132:oxidized very low density lipoprotein