Mycophenolate mofetil prevents the development of experimental autoimmune myocarditis.
Experimental autoimmune myocarditis (EAM) is characterized by the appearance of multinucleated giant cells. EAM leads to severe myocardial damage and is a useful model of human giant cell myocarditis. We investigated whether mycophenolate mofetil (MMF), which is a potent immunosuppressant, prevents the development of myocarditis in a rat EAM model, and focused on the role of osteopontin (OPN) in the pathogenesis of this disorder. Adult Lewis rats were immunized with porcine cardiac myosin to establish EAM. The early MMF treatment completely prevented the development of EAM, and the late MMF treatment was also effective even against established EAM. Echocardiogram demonstrated that left ventricular function was also improved by the treatment with MMF. Real-time RT-PCR analysis showed that both early and late MMF treatments significantly inhibited myocarditis-induced OPN mRNA expression in the heart. Immunohistochemistry revealed that OPN expression was prominent in the myocardium on day 14, whereas expression was observed in the infiltrated macrophages on day 21. Mycophenolic acid (MPA) did inhibit agonist-induced OPN expression in cultured cardiomyocytes. These results show the therapeutic potential of MMF for autoimmune myocarditis and provide new insights into the pathogenesis of this disease.
Division of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Yuichi
Y
Kamiyoshi
Masafumi
M
Takahashi
Osamu
O
Yokoseki
Yoshikazu
Y
Yazaki
Sho-Ichi
S
Hirose
Hajime
H
Morimoto
Noboru
N
Watanabe
Osamu
O
Kinoshita
Minoru
M
Hongo
Uichi
U
Ikeda
D000818:Animals; D000831:Animals, Newborn; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D001835:Body Weight; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004452:Echocardiography; D006352:Heart Ventricles / Q000166:cytology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009205:Myocarditis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D009929:Organ Size; D053495:Osteopontin; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000378:metabolism; D013997:Time Factors
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D009173:Mycophenolic Acid