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Right arrow Transplantation - heart

J Thorac Cardiovasc Surg 2007;134:780-788
© 2007 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Simvastatin attenuates cardiac isograft ischemia-reperfusion injury by down-regulating CC chemokine receptor-2 expression

Rong Yin, MD, Jiaquan Zhu, MD, Zhongqiu Wang, MD, Hairong Huang, MD, Jianjun Qian, MD, Zhongdong Li, MD, Hua Jing, MD*

Department of Cardiothoracic Surgery, Jinling Hospital, Clinical Medicine School of Nanjing University, Nanjing, China.

Received for publication December 1, 2006; revisions received April 19, 2007; accepted for publication May 2, 2007.

* Reprint requests: Hua Jing, MD, Department of Cardiothoracic Surgery, Jinling Hospital, Clinical Medicine School of Nanjing University, 305 East Zhongshan Road, Nanjing 210002, China. (Email: Jing_hua_1{at}yahoo.com.cn).

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.

Abbreviations and Acronyms CAL = coronary artery ligation; CCR2 = CC chemokine receptor-2; GGPP = geranylgeranyl pyrophosphate; ELISA = enzyme-linked immunosorbent assay; IR = ischemia-reperfusion; IRI = ischemia-reperfusion injury; MCP-1 = monocyte chemoattractant protein-1; MPO = myeloperoxidase; PCR = polymerase chain reaction






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