Lipoprotein(a), Homocysteine, and Atherogenesis

An elevated blood level of lipoprotein(a) is an independent risk factor for coronary and carotid artery atherosclerosis leading to premature myocardial infarction and stroke. Elevated liproprotein(a) is also associated with restenosis following coronary balloon angioplasty. The mechanisms by which lipoprotein(a) promote the atherosclerotic process are not clear. The apolipoprotein(a) portion of lipoprotein(a) shares partial homology with plasminogen, the precursor of plasmin, the fibrinolytic protease. Our studies have documented that lipoprotein(a) binds to fibrin, and that partial degradation of fibrin by plasmin increases binding. These findings parallel immunohistochemical studies showing colocalization of lipoprotein(a) with fibrin in atheromatous plaques, suggesting that the lipoprotein(a)-fibrin interaction may be atherogenic. We have found that homocysteine, at concentrations as low as 8 M, increased the binding of lipoprotein(a) to fibrin. Homocysteine induced a 20-fold increase in the affinity of lipoprotein(a) for plasmin-modified fibrin as compared to the binding in the absence of homocysteins. Our data indicate that homocysteine and other agents containing free sulfhydryl groups alter the lipoprotein(a) particle so as to increase the reactivity of the plasminogen-like apolipoprotein(a) portion. These observations suggest a biochemical link between lipoprotein(a), sulfhydryl compound metabolism, thrombosis, and atherogenesis.