title: Pitavastatin regulates helper T-cell differentiation and ameliorates autoimmune myocarditis in mice.
abstract: OBJECTIVE
  Experimental autoimmune myocarditis (EAM) is a mouse model of inflammatory cardiomyopathy, and the involvement of T helper (Th) 1 and Th17 cytokines has been demonstrated. Accumulated evidence has shown that statins have anti-inflammatory and immunomodulatory effects; however, the mechanism has not been fully elucidated. This study was designed to test the hypothesis that pitavastatin affects T cell-mediated autoimmunity through inhibiting Th1 and Th17 responses and reduces the severity of EAM in mice.
  
  
  METHODS
  The EAM model was established in BALB/c mice by immunization with murine α-myosin heavy chain. Mice were fed pitavastatin (5 mg/kg) or vehicle once daily for 3 weeks from day 0 to day 21 after immunization.
  
  
  RESULTS
  Pitavastatin reduced the pathophysiological severity of the myocarditis. Pitavastatin treatment inhibited the phosphorylation of signal transducer and activator of transcription (STAT)3 and STAT4, which have key roles in the Th1 and Th17 lineage commitment, respectively, in the heart, and suppressed production of Th1 cytokine interferon-γ and Th17 cytokine interleukin-17 from autoreactive CD4(+) T cells. In in vitro T-cell differentiation experiments, pitavastatin-treated T cells failed to differentiate into Th1 and Th17 cells through inhibiting the transcription of T-box expressed in T-cells (T-bet) and RAR-related orphan receptor γt (RORγT) which have critical roles in the development of Th1 and Th17 cells, respectively, and this failure was rescued by adding mevalonate.
  
  
  CONCLUSIONS
  Pitavastatin inhibits Th1 and Th17 responses and ameliorates EAM. These results suggest that statins may be a promising novel therapeutic strategy for the clinical treatment of myocarditis and inflammatory cardiomyopathy.
authors.affiliation: Cardiovascular Division, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan, ktajiri@md.tsukuba.ac.jp.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Tajiri
authors.forename: Nobutake
authors.initials: N
authors.lastname: Shimojo
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sakai
authors.forename: Tomoko
authors.initials: T
authors.lastname: Machino-Ohtsuka
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imanaka-Yoshida
authors.forename: Michiaki
authors.initials: M
authors.lastname: Hiroe
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tsujimura
authors.forename: Taizo
authors.initials: T
authors.lastname: Kimura
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yasutomi
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Aonuma
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020381:Interleukin-17; D011804:Quinolines; D007371:Interferon-gamma; C108475:pitavastatin