Factor XIIIa cross-links lipoprotein(a) with fibrinogen and is present in human atherosclerotic lesions.
During the development of atherosclerotic lesions, lipoprotein(a) [Lp(a)], a highly atherogenic lipoprotein, accumulates within fibrin clots attached to blood vessel walls. As Lp(a) accumulates within the fibrin clot with time, fatty streaks are formed that develop into occlusive atherosclerotic plaques. It is not understood, however, which mechanisms are involved in the binding of Lp(a) to fibrin and, hence, the stable incorporation of Lp(a) into the fibrin clot. The results of the present study demonstrate that factor XIIIa, a transglutaminase that catalyzes the formation of amide bonds between endo-gamma-glutaminyl and endo-epsilon-lysyl residues of proteins, is capable of cross-linking Lp(a) to fibrinogen, the soluble precursor of fibrin. Biochemical assays were conducted to demonstrate that factor XIIIa cross-links Lp(a) with fibrinogen in a time- and concentration-dependent manner. Additionally, immunohistochemical studies revealed that factor XIII protein expression colocalizes with Lp(a) expression in human atherosclerotic plaques. It is proposed that factor XIIIa-mediated cross-linking of Lp(a) to fibrin effectively increases the local concentration of Lp(a) within a fibrin clot. The accumulation of Lp(a) within the blood vessel promotes an antifibrinolytic environment, foam cell formation, the generation of a fatty streak, and an increase in smooth muscle cell content, all of which may contribute to the pathogenesis of atherosclerosis.
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA. anne_romanic-1@sbphrd.com
A M
AM
Romanic
A J
AJ
Arleth
R N
RN
Willette
E H
EH
Ohlstein
D001161:Arteriosclerosis / Q000378:metabolism*; D015153:Blotting, Western; D003432:Cross-Linking Reagents / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D017270:Lipoprotein(a) / Q000378:metabolism*; D011503:Transglutaminases / Q000378:metabolism*
D003432:Cross-Linking Reagents; D017270:Lipoprotein(a); D005337:Fibrin; D005340:Fibrinogen; D011503:Transglutaminases