Pitavastatin Suppresses Acute and Chronic Rejection in Murine Cardiac Allografts

Abstract

INTRODUCTION: HMG-CoA reductase inhibitors play several roles in the maintenance of organ transplants. We investigated the role of pitavastatin, a potent and newly developed HMG-CoA reductase inhibitor, in cardiac allograft rejection and mechanism of graft arterial disease (GAD) suppression. METHODS: Balb/c mice hearts were transplanted into C3H/He mice (a full allomismatch combination) to assess acute rejection or C57BL/6 hearts into B6.C-H2(<bm12>)KhEg (a class II mismatch combination) to examine the extent of GAD. Pitavastatin was administered orally to mice everyday (3 mg/kg/day). To assess the effect in acute rejection, mixed lymphocyte reaction was performed and cytokine mRNA expression was examined with ribonuclease protection assay. RESULTS: Pitavastatin significantly prolonged allograft survival. Lymphocyte proliferation was inhibited by pitavastatin, and RPA showed down-regulation of interleukin-6 in pitavastatin-treated cardiac allografts. Allografts in the pitavastatin-treated group after 8 weeks showed less GAD compared with the control group. In vitro, pitavastatin suppressed the smooth muscle cell proliferation in response to activated T cells and inhibited extracellular signal-regulated kinase 1/2 activation. CONCLUSION: Pitavastatin could be effective in the suppression of acute rejection and GAD development in cardiac transplantation.