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

Toyoharu Oba; Hideo Yasukawa; Takanobu Nagata; Sachiko Kyogoku; Tomoko Minami; Michihide Nishihara; Hideki Ohshima; Kazutoshi Mawatari; Shoichiro Nohara; Jinya Takahashi; Yusuke Sugi; Sachiyo Igata; Yoshiko Iwamoto; Hisashi Kai; Hidehiro Matsuoka; Makoto Takano; Hiroki Aoki; Yoshihiro Fukumoto; Tsutomu Imaizumi

doi:10.1253/circj.CJ-14-1171

Ischemic Heart Disease

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

Toyoharu Oba, Hideo Yasukawa, Takanobu Nagata, Sachiko Kyogoku, Tomoko Minami, Michihide Nishihara, Hideki Ohshima, Kazutoshi Mawatari, Shoichiro Nohara, Jinya Takahashi, Yusuke Sugi, Sachiyo Igata, Yoshiko Iwamoto, Hisashi Kai, Hidehiro Matsuoka, Makoto Takano, Hiroki Aoki, Yoshihiro Fukumoto, Tsutomu Imaizumi

Author information

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

Keywords: Cardioprotection, Erythropoietin, JAK-STAT, Remote ischemic preconditioning, Renal nerve

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Supplementary material

2015 Volume 79 Issue 7 Pages 1557-1567

DOI https://doi.org/10.1253/circj.CJ-14-1171

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Abstract

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. (Circ J 2015; 79: 1557–1567)

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