Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Basic Res Cardiol. 2012 Jul;107(4):277. doi: 10.1007/s00395-012-0277-1. Epub 2012 Jul 1.
Remote ischemic preconditioning (RIPC) induces a prolonged late phase of multi-organ protection against ischemia-reperfusion (IR) injury. In the present study, we tested the hypothesis that RIPC confers late protection against myocardial IR injury by upregulating expression of interleukin (IL)-10. Mice were exposed to lower limb RIPC or sham ischemia. After 24 h, mice with RIPC demonstrated decreased myocardial infarct size and improved cardiac contractility following 30-min ischemia and 120-min reperfusion (I-30/R-120). These effects of RIPC were completely blocked by anti-IL-10 receptor antibodies. In IL-10 knockout mice, RIPC cardioprotection was lost, but it was mimicked by exogenous IL-10. Administration of IL-10 to isolated perfused hearts increased phosphorylation of the protein kinase Akt and limited infarct size after I-30/R-120. In wild-type mice, RIPC increased plasma and cardiac IL-10 protein levels and caused activation of Akt and endothelial nitric oxide synthase in the heart at 24 h, which was also blocked by anti-IL-10 receptor antibodies. In the gastrocnemius muscle, RIPC resulted in immediate inactivation of the phosphatase PTEN and activation of Stat3, with increased IL-10 expression 24 h later. Myocyte-specific PTEN inactivation led to increased Stat3 phosphorylation and IL-10 protein expression in the gastrocnemius muscle. Taken together, these results suggest that RIPC induces late protection against myocardial IR injury by increasing expression of IL-10 in the remote muscle, followed by release of IL-10 into the circulation, and activation of protective signaling pathways in the heart. This study provides a scientific basis for the use of RIPC to confer systemic protection against IR injury.
远程缺血预处理 (RIPC) 可诱导多器官对缺血再灌注 (IR) 损伤的晚期保护作用。在本研究中，我们测试了 RIPC 通过上调白细胞介素 (IL)-10 的表达来提供晚期心肌 IR 损伤保护的假说。小鼠接受下肢 RIPC 或假缺血处理。24 小时后，RIPC 小鼠在 30 分钟缺血和 120 分钟再灌注 (I-30/R-120) 后表现出心肌梗死面积减小和心功能改善。RIPC 的这些作用完全被抗 IL-10 受体抗体阻断。在 IL-10 敲除小鼠中，RIPC 的心脏保护作用丧失，但外源性 IL-10 可模拟该作用。在离体灌注心脏中给予 IL-10 可增加蛋白激酶 Akt 的磷酸化，并在 I-30/R-120 后限制梗死面积。在野生型小鼠中，RIPC 增加了血浆和心脏中的 IL-10 蛋白水平，并在 24 小时时引起心脏中 Akt 和内皮型一氧化氮合酶的激活，这也被抗 IL-10 受体抗体阻断。在比目鱼肌中，RIPC 导致磷酸酶 PTEN 立即失活并激活 Stat3，24 小时后 IL-10 表达增加。肌细胞特异性 PTEN 失活导致比目鱼肌中 Stat3 磷酸化和 IL-10 蛋白表达增加。综上所述，这些结果表明，RIPC 通过增加远程肌肉中 IL-10 的表达来诱导对心肌 IR 损伤的晚期保护作用，随后将 IL-10 释放到循环中，并激活心脏中的保护信号通路。这项研究为 RIPC 用于提供全身对 IR 损伤的保护提供了科学依据。
