Mycophenolate mofetil treatment reduces atherosclerosis in the cholesterol-fed rabbit

Immune/inflammatory responses of arterial vessel wall constituents to lipid metabolic disturbances have been postulated to contribute to the pathogene sis of atherosclerosis. Mycophenolate mofetil (MMF), an antiproliferative a gent used in clinical transplantation, has been shown to inhibit smooth mus cle cell (SMC) proliferation and decrease the recruitment of monocytes into sites of chronic inflammation. This study was conducted to determine the e ffect of MMF on atherosclerotic plaque development after cholesterol-induce d injury. New Zealand white rabbits were fed a high-cholesterol diet contai ning 0.5% cholesterol and 8% peanut oil. The experimental group (n = 10) wa s given MMF (80 mg/kg/day subcutaneously); the control group (n = 10) recei ved placebo injections. The aortas were harvested at 12 weeks for immunohis tochemical analyses. SMCs were identified by reactivity with a monoclonal a ntibody (mAb) to alpha smooth muscle actin. Monocytes/macrophages were dete cted with mAb RAM 11. Cross-sectional areas of the media and neointima were measured using computer-assisted image analysis. The density of SMCs and m acrophage/foam cells within the neointima was calculated by dividing the nu mber of cells by the area of the plaque. Total cholesterol, triglyceride, h igh density lipoprotein, and low density lipoprotein were significantly inc reased compared with levels before the initiation of a high-cholesterol die t, but there were no significant differences between the MMF-treated and un treated groups, Neointimal area in aortic tissue sections of the MMF-treate d group (0.586 +/- 0.602 mm(2)) was significantly lower when compared with that in control animals (1.082 +/- 0.621 mm(2)) (P < 0.05). The densities o f neointimal SMCs and monocytes/macrophages in the control group were 778 /- 293 and 341 +/- 90 cells/mm(2), respectively. MMF treatment significantl y reduced the number of neointimal SMCs (506 +/- 185 cells/mm(2)) (P < 0.05 ). The number of monocytes/macrophages was also reduced after MMF treatment (260 +/- 124 cells/mm(2)) but not significantly. Our results demonstrate t hat the administration of MMF significantly reduced neointimal SMC accumula tion and plaque development in a hypercholesterolemic model of atherosclero sis. (C) 2000 Academic Press.