Rapamycin ameliorates experimental autoimmune myocarditis.
Myosin-induced autoimmune myocarditis in rats is a model of human dilated cardiomyopathy. Rapamycin is a potent immunosuppressant and specifically inactivates the mammalian target of rapamycin (mTOR). To examine the role of mTOR in autoimmune myocarditis, we administered rapamycin to rats immunized with cardiac myosin. Phosphorylation of p70 ribosomal S6 kinase 1 (S6K1), a target of mTOR, was increased by 6.9 fold in the heart tissue of myosin immunized rats. Rapamycin (2 mg/kg/day) completely suppressed S6K1 and S6 phosphorylation. The amount of interleukin-1beta, interferon-gamma, interleukin-2, or tumor necrosis factor-alpha mRNA in the heart tissue was markedly increased in myosin-immunized rats, and rapamycin significantly attenuated the cytokine gene expressions. Rapamycin improved the survival of the rats and preserved cardiac function. The plasma level of brain natriuretic peptide increased by 4.7 fold in myosin-immunized rats, and rapamycin attenuated the increase in plasma brain natriuretic peptide. The heart weight/tibial length ratio of vehicle-treated myosin-immunized rats was increased by 1.81 +/- 0.06 fold compared with vehicle-treated unimmunized rats, and rapamycin suppressed the increase in heart weight. Rapamycin decreased the cellular infiltration and fibrosis of the myocardium. The amount of phosphorylated S6 was increased in the infiltrating mononuclear cells in vehicle-treated myosin-immunized rats. Rapamycin significantly ameliorated myocardial injury and preserved cardiac function in a rat model of autoimmune myocarditis.
Maeda
Kayo
K
Department of Internal Medicine and Cardiology, Kitasato University School of Medicine, Sagamihara, Japan.
Shioi
Tetsuo
T
Kosugi
Rie
R
Yoshida
Yuki
Y
Takahashi
Keiko
K
Machida
Yoji
Y
Izumi
Tohru
T
D000818:Animals; D015551:Autoimmunity; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood; D007375:Interleukin-1 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D009205:Myocarditis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D009218:Myosins; D020097:Natriuretic Peptide, Brain / Q000097:blood; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000494:pharmacology*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007166:Immunosuppressive Agents; D007375:Interleukin-1; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D020097:Natriuretic Peptide, Brain; D007371:Interferon-gamma; D009218:Myosins; D020123:Sirolimus