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

• Oba Toyoharu

  Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine

• 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

• Takahashi Jinya

  Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine

• Sugi Yusuke

  Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine

• 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

抄録

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)

収録刊行物

• Circulation Journal

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

  一般社団法人 日本循環器学会

キーワード

• Cardioprotection
• Erythropoietin
• JAK-STAT
• Remote ischemic preconditioning
• Renal nerve

詳細情報

• CRID: 1390282680083651456
• NII論文ID: 130005083944
• NII書誌ID: AA11591968
• DOI: 10.1253/circj.cj-14-1171
• ISSN: 13474820
• ISSN: 13469843
• NDL書誌ID: 026523654
• PubMed: 25833080
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I026523654
• Web Site: https://www.jstage.jst.go.jp/article/circj/79/7/79_CJ-14-1171/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2015335496
• 本文言語コード: en
• データソース種別:
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