Simvastatin attenuates cardiac isograft ischemia-reperfusion injury by down-regulating CC chemokine receptor-2 expression.
OBJECTIVE
Accumulating evidence reveals that statins possess direct anti-inflammatory properties through inhibition of proinflammatory cytokine and chemokine secretion in addition to their antioxidant effects, which may contribute to amelioration of ischemia-reperfusion injury. This study tested the hypothesis that perioperative treatment of simvastatin suppresses the cardiac isograft ischemia-reperfusion injury by down-regulation of CC chemokine receptor-2 expression in an inbred rat model of cardiac transplantation.


METHODS
Donor hearts from Lewis rats were heterotopically transplanted to Lewis rat recipients. Recipients were orally treated with simvastatin (1 mg/kg) or vehicle every morning 3 days before the surgery until the harvest day. Rats were killed at 6 hours and at 1, 3, and 7 days after transplantation. Injury was assessed by infarct size measurement, histologic and immunohistochemical examination, and intragraft myeloperoxidase activity assay. Monocyte chemoattractant protein-1 levels in serum and graft were analyzed by enzyme-linked immunosorbent assay, and intragraft CC chemokine receptor-2 expression was measured by quantitative real-time polymerase chain reaction.


RESULTS
The infarct size and macrophage infiltration were all significantly reduced in the simvastatin-treated group compared with those of the control group at 1 day after transplantation. Neutrophil accumulation was significantly suppressed until 3 days after transplantation, whereas myeloperoxidase activity had been significantly diminished at 1 day after transplantation. Both monocyte chemoattractant protein-1 concentrations in serum and graft were remarkably decreased at 6 hours after transplantation. Intragraft CC chemokine receptor-2 expression was also down-regulated at 1 day and 3 days after transplantation.


CONCLUSIONS
Perioperative treatment of simvastatin could suppress the isograft ischemia-reperfusion injury through retarding intragraft monocyte chemoattractant protein-1 accumulation and CC chemokine receptor-2 expression.
Yin
Rong
R
Department of Cardiothoracic Surgery, Jinling Hospital, Clinical Medicine School of Nanjing University, Nanjing, China.
Zhu
Jiaquan
J
Wang
Zhongqiu
Z
Huang
Hairong
H
Qian
Jianjun
J
Li
Zhongdong
Z
Jing
Hua
H
D000818:Animals; D015536:Down-Regulation; D016027:Heart Transplantation / Q000009:adverse effects*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000209:etiology*; D019821:Simvastatin / Q000627:therapeutic use*
C515336:Ccr2 protein, rat; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D019821:Simvastatin