Pitavastatin suppresses acute and chronic rejection in murine cardiac allografts.
BACKGROUND
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.


CONCLUSIONS
Pitavastatin could be effective in the suppression of acute rejection and GAD development in cardiac transplantation.
Suzuki
Jun-ichi
J
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan. jsuzuki.cvm@tmd.ac.jp
Koga
Noritaka
N
Kosuge
Hisanori
H
Ogawa
Masahito
M
Haraguchi
Go
G
Maejima
Yasuhiro
Y
Saiki
Hitoshi
H
Isobe
Mitsuaki
M
D000208:Acute Disease; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D015996:Survival Rate; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology; D014280:Triglycerides / Q000097:blood
D016207:Cytokines; D007166:Immunosuppressive Agents; D011804:Quinolines; D014280:Triglycerides; D002784:Cholesterol; C108475:pitavastatin