ORIGINAL ARTICLE Pitavastatin Regulates Helper T-Cell Differentiation and Ameliorates Autoimmune Myocarditis in Mice Kazuko Tajiri & Nobutake Shimojo & Satoshi Sakai & Tomoko Machino-Ohtsuka & Kyoko Imanaka-Yoshida & Michiaki Hiroe & Yusuke Tsujimura & Taizo Kimura & Akira Sato & Yasuhiro Yasutomi & Kazutaka Aonuma # Springer Science+Business Media New York 2013 Abstract Purpose Experimental autoimmune myocarditis (EAM) is a mouse model of inflammatory cardiomyopathy, and the in- volvement of T helper (Th) 1 and Th17 cytokines has been demonstrated. Accumulated evidence has shown that statins have anti-inflammatory and immunomodulatory effects; how- ever, 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 phos- phorylation of signal transducer and activator of transcrip- tion (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 recep- tor γt (RORγT) which have critical roles in the develop- ment 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. Keywords Autoimmune myocarditis . Statin . Helper T cells . Inflammation Introduction Dilated cardiomyopathy (DCM) is a potentially lethal disorder of various etiologies for which no treatment is currently satis- factory [1]. Many patients show heart-specific autoantibodies [2, 3], and immunosuppressive therapy can improve their car- diac function [ 4]. These observations suggest that Electronic supplementary material The online version of this article (doi:10.1007/s10557-013-6464-y) contains supplementary material, which is available to authorized users. K. Tajiri (*) : N. Shimojo : S. Sakai : T. Machino-Ohtsuka : T. Kimura : A. Sato : K. Aonuma Cardiovascular Division, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan e-mail: ktajiri@md.tsukuba.ac.jp K. Tajiri : T. Machino-Ohtsuka : Y. Tsujimura : Y. Yasutomi Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Ibaraki, Japan K. Imanaka-Yoshida Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan K. Imanaka-Yoshida Mie University Matrix Biology Research Center, Mie University Graduate School of Medicine, Tsu, Mie, Japan M. Hiroe Department of Cardiology, National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan Y. Yasutomi Division of Immunoregulation, Department of Molecular and Experimental Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan Cardiovasc Drugs Ther DOI 10.1007/s10557-013-6464-y