Effects of atorvastatin on the Th1/Th2 polarization of ongoing experimental autoimmune myocarditis in Lewis rats.
OBJECTIVE
Experimental autoimmune myocarditis (EAM) in rats is a T cell-mediated disorder and the involvement of Th1/Th2 unbalance has been demonstrated. This study was designed to test the hypothesis that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, atorvastatin, affects T cell-mediated autoimmunity through modulating the balance of Th1/Th2 and reduces the severity of EAM.


METHODS
Myocarditis was induced in 23 Lewis rats by injection of porcine cardiac myosin. High-dose (10 mg/kg/day) or low-dose (1 mg/kg/day) atorvastatin or vehicle was administered orally for 3 weeks to rats with EAM at the same time of immunization. Seven Lewis rats received neither immunization nor statins therapy were used as normal controls. On day 21 after immunization (the climax of inflammation), echocardiography was examined and the severity of myocarditis was evaluated by histopathological evaluation. The area ratio (affected/entire area percentage) of myocardial lesions was determined in histological sections. Heart weight/body weight ratio was determined and the serum lipid levels were measured. Levels of serum IFN-gamma, IL-2, IL-4 and IL-10 were measured by ELISA.


RESULTS
Cardiac function was improved in the two atorvastatin-treated groups compared to the untreated group. Heart weight/body weight ratio and the degree of inflammation were significantly lower in the two dosage statin-treated groups than that in the untreated one. Furthermore, treatment with atorvastatin decreased the expression levels of Th1 cytokine (IFN-gamma and IL-2), and increased the expression levels of Th2 cytokine (IL-4 and IL-10). Atorvastatin attenuated the histopathological severity of myocarditis. Plasma lipid levels did not differ between the groups.


CONCLUSIONS
Atorvastatin ameliorates EAM by inhibiting T cell responses and suppressing Th1-type and inflammatory cytokines production and this activity is independent of cholesterol reduction, whereas Th2-type cytokines production was promoted. Atorvastatin may have beneficial effects on myocarditis by modulating the Th1/Th2 balance. These results demonstrate an important role of Th1/Th2 polarization in the pathogenesis of EAM and suggest that HMG-CoA reductase blockade may be a promising new strategy for the treatment of organ specific autoimmune diseases.
Liu
Wei
W
Department of Cardiology, The First Affiliated Hospital, Harbin Medical University, Heilongjiang 150001, China. doctor_liuwei@163.com
Li
Wei-Min
WM
Gao
Cheng
C
Sun
Ning-Ling
NL
D000818:Animals; D000069059:Atorvastatin; D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D020022:Genetic Predisposition to Disease; D006334:Heart Function Tests; D006538:Heptanoic Acids / Q000008:administration & dosage*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008297:Male; D009205:Myocarditis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage*; D051381:Rats; D011917:Rats, Inbred Lew; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin