Department of Cardiothoracic Surgery, Jinling Hospital, Clinical Medicine School of Nanjing University, 305 East Zhongshan Road, 210002 Nanjing, China.
Eur J Pharmacol. 2010 Dec 15;649(1-3):255-62. doi: 10.1016/j.ejphar.2010.08.058. Epub 2010 Sep 19.
Statins have been shown to downregulate the systemic inflammatory response after cardiopulmonary bypass. However, the role of statins as anti-inflammatory agents in heart tissue remains unknown. The aim of this study was to test whether statin pretreatment attenuates local inflammatory cytokines production in heart and to explore whether the underlying mechanism involves peroxisome proliferator-activated receptor (PPAR) γ. A rat model of cardiopulmonary bypass was established. The animals were pretreated with simvastatin 5 mg/kg/day or 10 mg/kg/day for 7 days before operation. The serum concentration and myocardial level of tumor necrosis factor (TNF)-α, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1 was evaluated by enzyme linked immunosorbent assay. The polymorphonuclear neutrophils accumulation in heart tissue was determined by myeloperoxidase activity assay. The activity of nuclear factor (NF)-κB and PPARγ in the heart was determined by electrophoretic mobility shift assay. The myocardial PPARγ expression was also examined by immunohistochemistry. The systemic and local TNF-α, IL-6 and MCP-1 were all significantly elevated after cardiopulmonary bypass. In contrast, simvastatin pretreatment significantly decreases the serum and myocardial expression level of above cytokines, myocardial myeloperoxidase activity and myocardial NF-κB activity. However, there was an evident increase in the activity and expression of PPARγ. In conclusion, simvastatin pretreatment not only attenuates acute systemic and local inflammatory response induced by cardiopulmonary bypass. The anti-inflammatory effect of simvastatin in myocardium may be partly related to the activation of PPARγ and inhibition of NF-κB.
他汀类药物已被证明可下调体外循环后的全身炎症反应。然而，他汀类药物作为抗炎药物在心脏组织中的作用尚不清楚。本研究旨在测试他汀类药物预处理是否能减弱心脏局部炎症细胞因子的产生，并探讨其潜在机制是否涉及过氧化物酶体增殖物激活受体（PPAR）γ。建立了体外循环大鼠模型。动物在手术前用辛伐他汀 5mg/kg/天或 10mg/kg/天预处理 7 天。通过酶联免疫吸附试验评估血清浓度和心肌肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6、单核细胞趋化蛋白（MCP）-1 的水平。通过髓过氧化物酶活性测定法测定中性粒细胞在心脏组织中的聚集。通过电泳迁移率变动测定法测定核因子（NF）-κB 和 PPARγ在心脏中的活性。还通过免疫组织化学法检查心肌 PPARγ的表达。体外循环后，全身和局部 TNF-α、IL-6 和 MCP-1 均明显升高。相比之下，辛伐他汀预处理可显著降低上述细胞因子的血清和心肌表达水平、心肌髓过氧化物酶活性和心肌 NF-κB 活性。然而，PPARγ的活性和表达明显增加。总之，辛伐他汀预处理不仅可减轻体外循环引起的急性全身和局部炎症反应，辛伐他汀在心肌中的抗炎作用可能部分与 PPARγ的激活和 NF-κB 的抑制有关。
