MYCOPHENOLATE MOFETIL PREVENTS TRANSPLANT ARTERIOSCLEROSIS BY DIRECT INHIBITION OF VASCULAR SMOOTH MUSCLE CELL PROLIFERATION1

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Abstract
Transplant arteriosclerosis is one of the main features of chronic graft failure in organ transplantation. In this article, the authors investigate mechanisms of mycophenolate mofetil (MMF) on prevention of transplant arteriosclerosis in a rat aortic allograft model. Orthotopic rat abdominal aortic transplantation was performed from Brown Norway (RT1n) to Lewis (RT1l) rats. The recipients were divided into three oral treatment groups: (1) vehicle; (2) MMF40 (40 mg/kg); and (3) MMF20 (20 mg/kg). The authors histologically and immunohistochemically evaluated neointima formation; infiltration of macrophages and T cells; and expression of endothelin (ET)-1, platelet-derived growth factor (PDGF)-B, PDGF receptor-β (Rβ), transforming growth factor (TGF) β1, and osteopontin (OPN). Using cultured rat vascular smooth muscle cells (VSMC), effects of mycophenolic acid (MPA) on ET-1–induced proliferation and ERK1/2 activation were also examined in vitro. In the vehicle group, marked neointima formation was observed, with massive macrophages and T-cell infiltration in neointima, media, and adventitia. Marked expression of ET-1, PDGF-B, PDGFR-β, TGFβ1, and OPN were also observed in neointima. In the MMF40 and MMF20 groups, neointima formation was halted, but macrophages and T cells were infiltrated in the adventitia and adhered to the endothelium. In the MMF40 group, medial infiltration by macrophages and T cells and intimal expression of ET-1, PDGF-B, PDGFR-β, TGFβ1, and OPN was inhibited compared with the vehicle and MMF20 groups. Furthermore, MPA inhibited ET-1–induced VSMC proliferation but failed to inhibit its ERK1/2 activation. MMF treatment might have preventive potential in transplant patients with chronic vasculopathy through inhibition of VSMC proliferation.