Renal Nerve-Mediated Erythropoietin Release Confers Cardioprotection During Remote Ischemic Preconditioning.
Renal Nerve-Mediated Erythropoietin Release Confers Cardioprotection During Remote Ischemic Preconditioning.
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DOI：
10.1253/circj.cj-14-1171
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发表时间：
2015-06
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通讯作者：
T. Oba;H. Yasukawa;Takanobu Nagata;S. Kyogoku;Tomoko Minami;M. Nishihara;Hideki Ohshima;Kazutoshi Mawatari;S. Nohara;J. Takahashi;Yusuke Sugi;S. Igata;Y. Iwamoto;H. Kai;H. Matsuoka;M. Takano;H. Aoki;Y. Fukumoto;T. Imaizumi
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作者：
T. Oba;H. Yasukawa;Takanobu Nagata;S. Kyogoku;Tomoko Minami;M. Nishihara;Hideki Ohshima;Kazutoshi Mawatari;S. Nohara;J. Takahashi;Yusuke Sugi;S. Igata;Y. Iwamoto;H. Kai;H. Matsuoka;M. Takano;H. Aoki;Y. Fukumoto;T. Imaizumi
背景短暂性肢体缺血诱导的远端缺血预适应(RIPC)是一种强大的先天心脏保护机制。一些已描述的机制解释了RIPC如何通过神经通路或体液因素发挥作用；然而，将远程器官连接到心脏的机制尚未完全阐明。本研究旨在通过建立小鼠和人的RIPC模型，研究RIPC诱导Janus激酶(JAK)信号转导和转录激活因子(STAT)激活的细胞因子的产生及其心脏保护的机制。方法和结果筛选小鼠循环心脏保护性JAK-STAT激活细胞因子，意外发现短暂性缺血诱导RIP后血清促红细胞生成素(EPO)水平升高。在小鼠中，RIPC迅速上调Epo mRNA及其主要转录因子低氧诱导因子-1α(HIF1α)在肾脏中的表达。激光多普勒血流仪显示RIPC后肾血流量(RBF)迅速减少。RIPC可激活心肌保护信号通路和抗细胞凋亡的Bclxl通路，减少心肌梗死面积。在小鼠身上，这些效应可通过注射促红细胞生成素中和抗体来消除。去肾神经也取消了RIPC诱导的RBF减少、EPO产生和心脏保护。在人类中，上臂短暂性肢体缺血降低了RBF，增加了血清EPO水平。结论在本研究的基础上，我们提出了一种新的肾缺血预适应机制，即肾缺血预适应通过激活HIF1α-EPO通路，通过肾神经介导的径向血流量减少来抑制心肌梗死面积。
BACKGROUND Remote ischemic preconditioning (RIPC) induced by transient limb ischemia is a powerful innate mechanism of cardioprotection against ischemia. Several described mechanisms explain how RIPC may act through neural pathways or humoral factors; however, the mechanistic pathway linking the remote organ to the heart has not yet been fully elucidated. This study aimed to investigate the mechanisms underlying the RIPC-induced production of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT)-activating cytokines and cardioprotection by using mouse and human models of RIPC. METHODS AND RESULTS Screened circulating cardioprotective JAK-STAT-activating cytokines in mice unexpectedly revealed increased serum erythropoietin (EPO) levels after RIP induced by transient ischemia. In mice, RIPC rapidly upregulated EPO mRNA and its main transcriptional factor, hypoxia-inducible factor-1α (HIF1α), in the kidney. Laser Doppler blood flowmetry revealed a prompt reduction of renal blood flow (RBF) after RIPC. RIPC activated cardioprotective signaling pathways and the anti-apoptotic Bcl-xL pathway in the heart, and reduced infarct size. In mice, these effects were abolished by administration of an EPO-neutralizing antibody. Renal nerve denervation also abolished RIPC-induced RBF reduction, EPO production, and cardioprotection. In humans, transient limb ischemia of the upper arm reduced RBF and increased serum EPO levels. CONCLUSIONS Based on the present data, we propose a novel RIPC mechanism in which inhibition of infarct size by RIPC is produced through the renal nerve-mediated reduction of RBF associated with activation of the HIF1α-EPO pathway.