Minimally oxidized low-density lipoprotein regulates hemostasis factors of brain capillary endothelial cells.
Minimally oxidized low-density lipoprotein (MM-LDL) is a potent atherogenic lipoprotein. We analyzed the effects of MM-LDL on brain capillary endothelial expression of plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (tPA), and thrombomodulin (TM). Cultured bovine brain capillary endothelial cells (BEC) incubated with MM-LDL (25 microg/ml) for 24 h showed increased PAI-1 mRNA levels by approximately seven-fold, while tPA and TM mRNA levels were reduced by 84% and 75%, respectively. Moreover, PAI-1 protein levels increased two-fold (16.8+/-7.6 vs. 7.6+/-2.1 ng/ml, p<0.05), whereas tPA protein levels decreased by 45% (1.3+/-0.5 ng/ml vs. 2.3+/-0.7 ng/ml, p<0.05), and TM protein level decreased by 40%. Following incubation with MM-LDL, PAI-1 activity was increased 35% (18.4+/-5.0 vs. 24.8+/-5.2 AU/ml, p<0.05), while TM activity was decreased by 30%. MM-LDL therefore has substantial pro-thrombotic effects on brain capillary endothelial cells, reducing both endothelial fibrinolytic capacity (downregulating tPA while upregulating PAI-1) and anticoagulant function (downregulating TM). These results suggest that MM-LDL may contribute to thrombus formation in the brain.
Kim
Jeong Ai
JA
Department of Neurology, University of California, Irvine, College of Medicine, 101 The City Drive South, Building. 55, Rm. 121, Orange, CA 92868-5120, USA. jkim8@uci.edu
Tran
Nam D
ND
Berliner
Judith A
JA
Fisher
Mark J
MJ
D000818:Animals; D001779:Blood Coagulation Factors / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000098:blood supply*; D002417:Cattle; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D020767:Intracranial Thrombosis / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D001779:Blood Coagulation Factors; D008077:Lipoproteins, LDL; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018180:Thrombomodulin; C099252:oxidized low density lipoprotein; D010959:Tissue Plasminogen Activator