Mycophenolate mofetil treatment reduces cholesterol-induced atherosclerosis in the rabbit

Immunosuppressive therapy has been shown to either improve or, more frequen tly, enhance the development of atherosclerosis. We tested the effect of my cophenolate mofetil (MMF), an inhibitor of nucleotide synthesis widely used in transplant therapy, in diet-induced atherosclerosis in the rabbit. Two groups (n = 10 each) of New Zealand White (NZW) rabbits were fed a 1% chole sterol diet for 12 weeks. One group received MMF (CHOL + MMF group) by gast ric gavage (30 mg/kg daily) and the other group (CHOL) received the same vo lume of saline by the same route. There were no differences in the serum ch olesterol (mean values greater than or equal to 30 mmol/l in both groups af ter 2 weeks) or in the triglyceride, blood sugar, total protein, and albumi n serum levels and weight gain in both groups of animals. The cholesterol-f ed untreated rabbits had atherosclerotic plaques covering 43.9.1 +/- SD 16. 40% of their thoracic aorta and 41.9 +/- 22.59% of their abdominal aorta, w hile the MMF treated group had 18.5 +/- 7.17% and 17.7 +/- 9.71%, respectiv ely (P < 0.01). The cholesterol content of the aorta (mg/g) in the choleste rol-fed untreated group was 4.61 +/- SD 1.21 in the thoracic aorta and 4.54 +/- 2.07 in the abdominal aorta, whereas the MMF treated group had and 2.8 3 +/- 0.84 and 2.77 +/- 1.44, respectively (P < 0.01). Infiltrating macroph ages (RAM 11 positive cells/100 nuclei) in the intimal layer of the aorta w ere 58.4 +/- SD26.16 in the CHOL group and 8.5 +/- 5.51 in the CHOL + MMF g roup: (P < 0.001). CD18 positive cells/100 nuclei were 27.4 +/- 17.6 in the CHOL group and 5.3 +/- 3.82 in the CHOL + MMF group (P < 0.01), and the in tima/media ratio was 0.66 +/- 0.11 in the CHOL group and 0.30 +/- 0.09 in t he MMF treated rabbits (P < 0.001). MMF also reduced proliferating smooth m uscle cells (HHF35 positive) infiltrating between the macrophages. These re sults indicate that MMF ameliorates importantly the atherogenic potential o f a high cholesterol diet and this effect is associated with a reduction in macrophage and foam cell infiltration and smooth muscle cell proliferation and infiltration. Since chronic treatment with this drug is given routinel y in various clinical conditions with relatively minor side effects, consid eration may be given to its use as adjuvant therapy in artheriosclerotic ca rdiovascular disease. (C) 2000 Elsevier Science Ireland Ltd. All rights res erved.