title: Glycation amplifies lipoprotein(a)-induced alterations in the generation of fibrinolytic regulators from human vascular endothelial cells.
abstract: Increased lipoprotein(a) [Lp(a)] in plasma is an independent risk factor for premature cardiovascular diseases. The levels of glycated Lp(a) are elevated in diabetic patients. The present study demonstrated that glycation enhanced Lp(a)-induced production of plasminogen activator inhibitor-1 (PAI-1), and further decreased the generation of tissue-type plasminogen activator (t-PA) from human umbilical vein endothelial cells (HUVEC) and human coronary artery EC. The levels of PAI-1 mRNA and its antigen in the media of HUVEC were significantly increased following treatments with 5 microgram/ml of glycated Lp(a) compared to equal amounts of native Lp(a). The secretion and de novo synthesis of t-PA, but not its mRNA level, in EC were reduced by glycated Lp(a) compared to native Lp(a). Treatment with aminoguanidine, an inhibitor for the formation of advanced glycation end products (AGEs), during glycation normalized the generation of PAI-1 and t-PA induced by glycated Lp(a). Butylated hydroxytoluene, a potent antioxidant, inhibited native and glycated Lp(a)-induced changes in PAI-1 and t-PA generation in EC. The results indicate that glycation amplifies Lp(a)-induced changes in the generation of PAI-1 and t-PA from venous and arterial EC. This may attenuate fibrinolytic activity in blood circulation and potentially contributes to the increased incidence of cardiovascular complications in diabetic patients with hyperlipoprotein(a). EC-mediated oxidative modification and the formation of AGEs may be implicated in glycated Lp(a)-induced alterations in the generation of fibrinolytic regulators from vascular EC.
authors.affiliation: Departments of Internal Medicine and Physiology, The University of Manitoba, BS440 730 William Ave, Manitoba, R3E 3J7, Winnipeg, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Ren
authors.forename: G X
authors.initials: GX
authors.lastname: Shen
mesh_terms: D015415:Biomarkers / Q000097:blood; D015152:Blotting, Northern; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology / Q000473:pathology; D002478:Cells, Cultured; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000097:blood; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006031:Glycosylation; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D017270:Lipoprotein(a) / Q000187:drug effects / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D010959:Tissue Plasminogen Activator; C004479:pimagedine