Lipoprotein(a) [Lp(a)] is a cholesterol-rich macromolecule consisting of a low-density lipoprotein (LDL) particle linked to a characteristic apolipoprotein [apo(a)]. In numerous epidemiolgic studies, Lp(a) has been shown to be associated with increased incidence of cardiovascular disease, with plasma levels of above 30 mg/dl imparting a greater than twofold increases in risk in the Caucasian population. In addition, since the plasma level of Lp(a) is strongly and inversely governed by the size of the apo(a) gene, it accounts for a major portion of the inherited susceptibility to atherosclerotic disease. However, several fundamental questions concerning this epidemilogic observation remain to be addressed. First, the pathogenic mechanism(s) of underlying the link between Lp(a) and atherosclerosis is largely unknown. Furthermore, the significance of high Lp(a) levels in non-Caucasion populations such as African Americans and Hispanics remains unclear. This question is of particular importance in African Americans who have higher Lp(a) levels than Caucasians. Finally, no effective therapy currently exists to lower Lp(a) levels. Recently, using high resolution ultrasound, we found elevated Lp(a) levels to be independently associated with impaired endothelium-dependent, flow-mediated dilation of the brachial artery in racially-mixed group of 119 subjects. These findings provide evidence that Lp(a)'s atherogenicity is at least in part mediated by damaging effects on the vascular endothelium, and that this adverse effect may not be limited to Caucasians. In this project, a series of clinical studies is proposed to further delineate the role of Lp(a) in endothelial dyusfunction. Specific hypotheses are (1) Lp(a) levels greater than 30 mg/dl are associated with impaired endothelial-dependent, flow-mediated dilation in the Caucasian and Hispanic subjects but not in African Americans; (2) small apo(a) sizes of less than 22 kringle-4 units rather than high Lp(a) levels are more strongly associated with impaired dilation in African Americans; and (3) endothelial dysfunction related to Lp(a) can be reversed by oral supplementation with either L-arginine or vitamin E. Since endothelial dysfunction represents a critical event in atherogenesis, this project will provide important insights into the pathobiology of Lp(a) as well as clarify the significance of its interracial variations and explore potential therapeutic approaches.
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