HMG-CoA reductase inhibitor attenuates experimental autoimmune myocarditis through inhibition of T cell activation.
OBJECTIVE
This study tested the hypothesis that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor affects T cell-mediated autoimmunity through inhibition of nuclear factor-kappaB (NFkappaB) and reduces the severity of experimental autoimmune myocarditis (EAM).


METHODS
EAM was induced in Lewis rats by immunization with myosin. High-dose or low-dose fluvastatin or vehicle was administered orally for 3 weeks to rats with EAM.


RESULTS
Fluvastatin reduced the pathophysiological severity of myocarditis. Fluvastatin inhibited expression of NFkappaB in the nuclei of myocardium in EAM. Fluvastatin reduced production of Th1-type cytokines, including interferon (IFN)-gamma and interleukin (IL)-2, and inhibited expression of inflammatory cytokine mRNAs in the myocardium. Infiltration of CD4-positive T cells into the myocardium and T cell proliferative responses were suppressed by fluvastatin. Plasma lipid levels did not differ between the groups.


CONCLUSIONS
Fluvastatin ameliorates EAM by inhibiting T cell responses and suppressing Th1-type and inflammatory cytokines via inactivation of nuclear factor-kappaB, and this activity is independent of cholesterol reduction.
Azuma
Ryoko Wakizono
RW
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Suzuki
Jun-ichi
J
Ogawa
Masahito
M
Futamatsu
Hideki
H
Koga
Noritaka
N
Onai
Yasuyuki
Y
Kosuge
Hisanori
H
Isobe
Mitsuaki
M
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D015153:Blotting, Western / Q000379:methods; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D023421:Models, Animal; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology; D009206:Myocardium / Q000378:metabolism; D009218:Myosins / Q000008:administration & dosage; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology*
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007376:Interleukin-2; D016328:NF-kappa B; D000077340:Fluvastatin; D007371:Interferon-gamma; D009218:Myosins