Mycophenolate mofetil prevents transplant arteriosclerosis by direct inhibition of vascular smooth muscle cell proliferation.
BACKGROUND.: 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.


METHODS
Orthotopic rat abdominal aortic transplantation was performed from Brown Norway (RT1) to Lewis (RT1) 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-beta (Rbeta), transforming growth factor (TGF) beta 1, 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.


RESULTS
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-beta, TGFbeta1, 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-beta, TGFbeta1, 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.


CONCLUSIONS
MMF treatment might have preventive potential in transplant patients with chronic vasculopathy through inhibition of VSMC proliferation.
Shimizu
Hisashi
H
Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
Takahashi
Masafumi
M
Takeda
Shin-Ichi
S
Inoue
Seiichiro
S
Fujishiro
Jun
J
Hakamata
Yoji
Y
Kaneko
Takashi
T
Murakami
Takashi
T
Takeuchi
Koichi
K
Takeyoshi
Izumi
I
Morishita
Yasuo
Y
Kobayashi
Eiji
E
D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology* / Q000637:transplantation*; D001018:Aortic Diseases / Q000517:prevention & control*; D001161:Arteriosclerosis / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D019332:Endothelin-1; D006133:Growth Substances; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid