Journal
CIRCULATION JOURNAL
Volume 79, Issue 7, Pages 1557-U392Publisher
JAPANESE CIRCULATION SOC
DOI: 10.1253/circj.CJ-14-1171
Keywords
Cardioprotection; Erythropoietin; JAK-STAT; Remote ischemic preconditioning; Renal nerve
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Funding
- grant for the Science Frontier Research Promotion Centers (Cardiovascular Research Institute)
- Ministry of Education, Science, Sports, and Culture, Japan
- Kimura Memorial Heart Foundation
- Japanese Ministry of Health, Labour and Welfare Research Grant
- Grants-in-Aid for Scientific Research [26670292] Funding Source: KAKEN
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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-1 alpha (HIF1 alpha), 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 HIF1 alpha-EPO pathway.
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