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Pitavastatin Regulates Helper T-Cell Differentiation and Ameliorates Autoimmune Myocarditis in Mice

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Abstract

Purpose

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.

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Acknowledgments

We are grateful to Brian Purdue of the Medical English Communications Center of the University of Tsukuba for revising this manuscript. This work was supported by the University of Tsukuba Research Infrastructure Support Program.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Cardiovascular Division, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Kazuko Tajiri, Nobutake Shimojo, Satoshi Sakai, Tomoko Machino-Ohtsuka, Taizo Kimura, Akira Sato & Kazutaka Aonuma

  2. Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Ibaraki, Japan

    Kazuko Tajiri, Tomoko Machino-Ohtsuka, Yusuke Tsujimura & Yasuhiro Yasutomi

  3. Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie, Japan

    Kyoko Imanaka-Yoshida

  4. Mie University Matrix Biology Research Center, Mie University Graduate School of Medicine, Tsu, Mie, Japan

    Kyoko Imanaka-Yoshida

  5. Department of Cardiology, National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan

    Michiaki Hiroe

  6. Division of Immunoregulation, Department of Molecular and Experimental Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan

    Yasuhiro Yasutomi

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  1. Kazuko Tajiri
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  2. Nobutake Shimojo
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Correspondence to Kazuko Tajiri.

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Tajiri, K., Shimojo, N., Sakai, S. et al. Pitavastatin Regulates Helper T-Cell Differentiation and Ameliorates Autoimmune Myocarditis in Mice. Cardiovasc Drugs Ther 27, 413–424 (2013). https://doi.org/10.1007/s10557-013-6464-y

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