Impact of diabetes-associated lipoproteins on generation of fibrinolytic regulators from vascular endothelial cells.
Increased thrombotic tendency and decreased fibrinolytic activity have been frequently found in patients with diabetes mellitus (DM). Previous studies by our group indicated that nonenzymatically glycated low density lipoprotein (LDL) increased plasminogen activator inhibitor-1 (PAI-1) production and decreased the generation of tissue plasminogen activator (tPA) from cultured human umbilical vein endothelial cells (HUVEC). The present study demonstrates that plasma levels of PAI-1 or PAI-1/tPA were significantly increased in patients with type 1 (n = 10) and type 2 DM (n = 14) compared with those in healthy controls (n = 10; P < 0.05 or 0.01). LDL from patients with type 1 or type 2 DM, and very low density lipoprotein (VLDL) from patients with type 2 DM induced significantly greater increases in the release of PAI-1 and more profound reduction in tPA generation from HUVEC compared with corresponding lipoproteins from healthy controls (P < 0.05 or 0.01). HDL from diabetic patients did not significantly alter the generation of PAI-1 or tPA from endothelial cells (EC) compared with HDL from controls. Comparable effects of lipoproteins from DM patients on the generation of PAI-1 and tPA were found in human coronary artery EC. LDL and VLDL from patients with type 2 DM enhanced the activation of PAI-1 promoter (-1528/+55)/luciferase reporter gene transiently transfected in HUVEC (P < 0.01). The results of the present study suggest that LDL and VLDL from patients with DM reduce the generation of tPA and increase PAI-1 production through the activation of the PAI-1 promoter in vascular EC.
Ren
Song
S
Diabetes Research Group, University of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada.
Lee
Harvey
H
Hu
Limei
L
Lu
Lin
L
Shen
Garry X
GX
D000328:Adult; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000097:blood / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008079:Lipoproteins, VLDL / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D011401:Promoter Regions, Genetic; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D014162:Transfection
D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator