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 fibri n clot with time, fatty streaks are formed that develop into occlusive atherosclerotic plaques. It is not understood, however, which mechani sms are involved in the binding of Lp(a) to fibrin and, hence, the sta ble incorporation of Lp(a) into the fibrin clot. The results of the pr esent study demonstrate that factor XIIIa, a transglutaminase that cat alyzes the formation of amide bonds between endo-gamma-glutaminyl and endo-E-lysyl residues of proteins, is capable of cross-linking Lp(a) t o fibrinogen, the soluble precursor of fibrin. Biochemical assays were conducted to demonstrate that factor XIIIa cross-links Lp(a) with fib rinogen in a time- and concentration-dependent manner. Additionally, i mmunohistochemical studies revealed that factor XIII protein expressio n colocalizes with Lp(a) expression in human atherosclerotic plaques. It is proposed that factor XIIIa-mediated cross-linking of Lp(a) to fi brin effectively increases the local concentration of Lp(a) within a f ibrin 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.