Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis.
Lipoprotein (a) (Lp(a)) is a low density lipoprotein-like particle which contains the plasminogen-like apolipoprotein a. Lp(a) levels are elevated in patients with atherosclerotic coronary artery disease. Recent studies suggest that Lp(a) competitively inhibits plasminogen binding to the endothelial cell and interferes with surface-associated plasmin generation. In this study, we present evidence for the presence of Lp(a) in the microvasculature of inflamed tissue. In addition, we demonstrate that Lp(a) regulates endothelial cell synthesis of a major fibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1). In cultured human endothelial cells, Lp(a) enhanced PAI-1 antigen, activity, and steady-state mRNA levels without altering tissue plasminogen activator activity or mRNA transcript levels. This effect was cell-specific. Although other lipoproteins did not coordinately raise PAI-1 mRNA levels in endothelial cells, low density lipoprotein treatment selectively raised the level of the 3.4-kilobase mRNA species of PAI-1 without a concomitant increase in PAI-1 activity or antigen. Endothelial cell exposure to Lp(a) did not cause generalized endothelial cell activation since the functional activity and mRNA levels for tissue factor, platelet-derived growth factor and interleukin-6 were not elevated following Lp(a) exposure. These data suggest a molecular mechanism whereby Lp(a) may support a specific prothrombotic endothelial cell phenotype, namely by increasing PAI-1 expression.
Etingin
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OR
Department of Medicine, Cornell University Medical College, New York, New York 10021.
Hajjar
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DP
Hajjar
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KA
Harpel
P C
PC
Nachman
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D002460:Cell Line; D004730:Endothelium, Vascular / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics; D007700:Kinetics; D017270:Lipoprotein(a); D008074:Lipoproteins / Q000378:metabolism*; D015849:Plasminogen Inactivators / Q000276:immunology / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics; D013927:Thrombosis / Q000209:etiology; D010959:Tissue Plasminogen Activator / Q000032:analysis
D015850:Interleukin-6; D017270:Lipoprotein(a); D008074:Lipoproteins; D015849:Plasminogen Inactivators; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D013925:Thromboplastin; D010959:Tissue Plasminogen Activator