Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis.
Endothelial cells play a critical role in thromboregulation by virtue of a surface-connected fibrinolytic system. Cultured endothelial cells synthesize and secrete tissue-type plasminogen activator (t-PA) which can bind to at least two discrete sites on the cell surface. These binding sites preserve the catalytic activity of t-PA and protect it from its physiological inhibitor (PAI-1). N-terminal glutamic acid plasminogen (Glu-PLG), the main circulating fibrinolytic zymogen, also interacts specifically with the endothelial cell surface. Binding is associated with a 12-fold increase in catalytic efficiency of plasmin generation by t-PA which may reflect conversion of Glu-PLG to its plasmin-modified form, N-terminal lysine plasminogen (Lys-PLG). Lipoprotein(a) is an atherogenic lipoprotein particle which contains the plasminogen-like apolipoprotein(a) bound to low density lipoprotein. We report here that lipoprotein(a) interferes with endothelial cell fibrinolysis by inhibiting plasminogen binding and hence plasmin generation. In addition, we demonstrate lipoprotein(a) accumulation in atherosclerotic lesions. These findings may provide a link between impaired cell surface fibrinolysis and progressive atherosclerosis.
Hajjar
K A
KA
Department of Pediatrics, Cornell University Medical College, New York, New York 10021.
Gavish
D
D
Breslow
J L
JL
Nachman
R L
RL
D001053:Apolipoproteins / Q000378:metabolism; D053241:Apoprotein(a); D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000473:pathology; D004730:Endothelium, Vascular / Q000502:physiology*; D005342:Fibrinolysis; D006801:Humans; D007700:Kinetics; D017270:Lipoprotein(a); D008074:Lipoproteins / Q000032:analysis / Q000097:blood / Q000502:physiology*; D012501:Saphenous Vein / Q000473:pathology / Q000637:transplantation; D014471:Umbilical Veins
D001053:Apolipoproteins; D002352:Carrier Proteins; D017270:Lipoprotein(a); D008074:Lipoproteins; D053241:Apoprotein(a)