title: Renal Nerve-Mediated Erythropoietin Release Confers Cardioprotection During Remote Ischemic Preconditioning.
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.
  
  
  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.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine.
authors.forename: Toyoharu
authors.initials: T
authors.lastname: Oba
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nagata
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kyogoku
authors.forename: Tomoko
authors.initials: T
authors.lastname: Minami
authors.forename: Michihide
authors.initials: M
authors.lastname: Nishihara
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohshima
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Mawatari
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Nohara
authors.forename: Jinya
authors.initials: J
authors.lastname: Takahashi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sugi
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Igata
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kai
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Matsuoka
authors.forename: Makoto
authors.initials: M
authors.lastname: Takano
authors.forename: Hiroki
authors.initials: H
authors.lastname: Aoki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D004921:Erythropoietin / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D053612:Janus Kinases / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000294:innervation* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D010525:Peripheral Nerves / Q000378:metabolism* / Q000503:physiopathology; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494812:Bcl2l1 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051020:bcl-X Protein; D004921:Erythropoietin; D053612:Janus Kinases