Renal Nerve-Mediated Erythropoietin Release Confers Cardioprotection During Remote Ischemic Preconditioning

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Author(s)

    • Igata Sachiyo
    • Division of Integrated Autonomic Function, Department of Physiology, Kurume University School of Medicine
    • Iwamoto Yoshiko
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
    • Kai Hisashi
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
    • Matsuoka Hidehiro
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
    • Takano Makoto
    • Division of Integrated Autonomic Function, Department of Physiology, Kurume University School of Medicine
    • Aoki Hiroki
    • Cardiovascular Research Institute, Kurume University
    • Fukumoto Yoshihiro
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine|Cardiovascular Research Institute, Kurume University
    • Imaizumi Tsutomu
    • Fukuoka Sanno Hospital and International University of Health and Welfare
    • Yasukawa Hideo
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine|Cardiovascular Research Institute, Kurume University
    • Nagata Takanobu
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
    • Kyogoku Sachiko
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
    • Minami Tomoko
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
    • Nishihara Michihide
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
    • Ohshima Hideki
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
    • Mawatari Kazutoshi
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
    • Nohara Shoichiro
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine

Abstract

<b><i>Background:</i></b>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.<b><i>Methods and Results:</i></b>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.<b><i>Conclusions:</i></b>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. (<i>Circ J</i> 2015; <b>79:</b> 1557–1567)

Journal

  • Circulation Journal

    Circulation Journal 79(7), 1557-1567, 2015

    The Japanese Circulation Society

Codes

  • NII Article ID (NAID)
    130005083944
  • NII NACSIS-CAT ID (NCID)
    AA11591968
  • Text Lang
    ENG
  • ISSN
    1346-9843
  • NDL Article ID
    026523654
  • NDL Call No.
    Z54-B860
  • Data Source
    NDL  J-STAGE 
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