INHIBITION OF HYPERCHOLESTEROLEMIA-INDUCED ATHEROSCLEROSIS IN THE NONHUMAN PRIMATE BY PROBUCOL .2. CELLULAR COMPOSITION AND PROLIFERATION

In nonhuman primates (Macaca nemestrina) treated with the antioxidant probucol during diet-induced hypercholesterolemia, intimal lesion area in the thoracic aorta was decreased, with increased resistance of pla sma LDL to oxidation. The cellular and molecular changes associated wi th the decrease in lesion size in the probucol-treated hypercholestero lemic animals are quantitatively evaluated in this study. Lesions from the probucol-treated animals appear less mature and have altered lipi d distribution. Abundant lipid-laden smooth muscle cells are found in the intima and media of the probucol-treated animals, with fewer media l lipid-laden macrophages, compared with lesions at similar sites in t he control hypercholesterolemic animals. In both the control and probu col-treated animals, macrophages are the predominant cells in most les ions, but the ratio of macrophages to smooth muscle cells is decreased in the lower thoracic and upper abdominal aortic sites in the probuco l-treated animals. Lesions at all aortic sites in the probucol-treated animals have a 35% to 80% reduction in the percentage of cells in cel l cycle traverse, as indicated by immunostaining for proliferating cel l nuclear antigen (% PCNA-positive). In both groups, macrophages and s mooth muscle cells are PCNA-positive, but the majority (>60%) are macr ophages. No difference in % PCNA-positive cells is seen in the iliac a rteries, where the most advanced lesions were present at the time prob ucol administration was initiated. Limited Northern analysis of growth -regulatory molecules possibly involved in the cellular changes associ ated with lesions shows a 30% to 50% decrease in mRNA levels of platel et-derived growth factor (PDGF) B-chain, PDGF beta-receptor, colony-st imulating factor type 1, and monocyte chemotactic protein 1. Thus, a p otential role for an antioxidant such as probucol in the treatment of atherosclerosis may be to alter the early inflammatory fibroproliferat ive processes of the disease. Whether these effects are directly relat ed to the antioxidant properties or some other activity of probucol is not yet known.