Erythropoietin alleviates post-ischemic injury of rat hearts by attenuating nitrosative stress

Ming Jen Lu, Yih Sharng Chen, Ho Shiang Huang, Ming Chieh Ma

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Aims: Nitrosative stress caused by ischemia contributes to poor functional recovery in hearts. A previous study showed that recombinant human erythropoietin (EPO) activates the Janus-tyrosine kinase 2/extracellular signal-regulated kinase (Jak2/ERK) pathway to protect myocardium against ischemia/reperfusion (IR) injury. However, it is not clear how pro-survival signals triggered by EPO affect the nitric oxide (NO) system in post-ischemic myocardial tissue. Main methods: Isolated rat hearts were subjected to IR injury and changes in protein expression in the myocardium were evaluated by immunostaining. Key findings: Compared with untreated hearts, EPO-treated IR hearts showed significant improvements in contractility and reduced myocardial injury and infarction; this was associated with attenuated caspase-3 activation. Excess formation of NO metabolites and nitrotyrosine, which cause nitrosative stress, was markedly suppressed by EPO. The mechanism underlying EPO-mediated alleviation of nitrosative stress was related to an increase in arginase II expression and to the suppression of heat shock protein 90 (HSP90)-dependent upregulation of endothelial and inducible NO synthase (NOS). Myocardial EPO content was restored after EPO treatment, which in turn recruited signal transducer and activator of transcription (STAT) 3 protein and induced ERK signaling downstream of Jak2, which increased arginase II levels and suppressed HSP90 expression, respectively. Inhibition of STAT3 and ERK specifically reversed the effects of EPO on arginase II and HSP90 expression. Significance: These results indicate that EPO triggers the Jak2-STAT3/ERK pathway to restore the balance between arginase and NOS and, thus, reduces nitrosative stress. This may form the basis of myocardial protection following IR.

Original languageEnglish
Pages (from-to)776-784
Number of pages9
JournalLife Sciences
Volume90
Issue number19-20
DOIs
Publication statusPublished - 2012 May 22

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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