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 pathogenesis of atherosclerosis. Mycophenolate mofetil (MMF), an antiproliferative agent used in clinical transplantation, has been shown to inhibit smooth muscle cell (SMC) proliferation and decrease the recruitment of monocytes into sites of chronic inflammation. This study was conducted to determine the effect of MMF on atherosclerotic plaque development after cholesterol-induced injury. New Zealand white rabbits were fed a high-cholesterol diet containing 0.5% cholesterol and 8% peanut oil. The experimental group (n = 10) was given MMF (80 mg/kg/day subcutaneously); the control group (n = 10) received placebo injections. The aortas were harvested at 12 weeks for immunohistochemical analyses. SMCs were identified by reactivity with a monoclonal antibody (mAb) to alpha smooth muscle actin. Monocytes/macrophages were detected with mAb RAM 11. Cross-sectional areas of the media and neointima were measured using computer-assisted image analysis. The density of SMCs and macrophage/foam cells within the neointima was calculated by dividing the number of cells by the area of the plaque. Total cholesterol, triglyceride, high density lipoprotein, and low density lipoprotein were significantly increased compared with levels before the initiation of a high-cholesterol diet, but there were no significant differences between the MMF-treated and untreated groups. Neointimal area in aortic tissue sections of the MMF-treated 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 of neointimal SMCs and monocytes/macrophages in the control group were 778 +/- 293 and 341 +/- 90 cells/mm(2), respectively. MMF treatment significantly 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 that the administration of MMF significantly reduced neointimal SMC accumulation and plaque development in a hypercholesterolemic model of atherosclerosis.
Greenstein
S M
SM
Department of Surgery, Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, 111 East 210th Street, Bronx, New York 10467, USA. SGreenst@montefiore.org
Sun
S
S
Calderon
T M
TM
Kim
D Y
DY
Schreiber
T C
TC
Schechner
R S
RS
Tellis
V A
VA
Berman
J W
JW
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001161:Arteriosclerosis / Q000139:chemically induced* / Q000473:pathology*; D002791:Cholesterol, Dietary; D008264:Macrophages / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D002791:Cholesterol, Dietary; D009173:Mycophenolic Acid