Lp[a] is a lipoprotein whose plasma concentration is highly correlated with cardiovascular and cerebrovascular disease. Lp[a] resembles low density lipoprotein except that it contains an additional glycoprotein, apo[a], that occurs in many polymorphic forms of differing apparent molecular weight (Mr). The broad objective of this project is to determine the role that Lp[a] composition (apo[a] size, carbohydrate content, triglyceride content) might have on the in vitro and in vivo metabolism of Lp[a], and on the capacity of Lp[a] to influence the reactivity of vascular cells. This objective will be pursued through six areas of focus: 1) The synthesis of apo[a] in human subjects with different Mr forms of the protein will be measured by stable isotope methodology. 2) The catabolism of Lp[a] containing apo[a] of differing Mr will be studied in human subjects, as well as in cultured fibroblasts, hepatocytes, and umbilical vein endothelial cells. 3) The dependence of Lp[a] catabolism on the carbohydrate content of the lipoprotein will be studied in cultured macrophages and arterial subendothelial cells, and in whole animals. 4) The formation and lipolysis of triglyceride-rich Lp[a] will be studied in normal Black and White subjects, and in patients with fasting hypertriglyceridemia. 5) The effect of Lp[a] on blood vessel tone and the production of nitric oxide by the vascular endothelium and smooth muscle will be measured on aortic and coronary vessel rings. 6) The effect of Lp[a] on the proliferative and synthetic activity of cultured vascular endothelial and smooth muscle cells will be studied. These studies should provide new insights into the role(s) played by Lp[a] in the pathogenesis of atherosclerosis and vascular disease.
