IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2

Buddhadeb Dawn, Yu Ting Xuan, Yiru Guo, Arash Rezazadeh, Adam B. Stein, Greg Hunt, Wen Jian Wu, Wei Tan, Roberto Bolli

Research output: Contribution to journalArticle

Abstract

Objective: We sought to determine whether interleukin (IL)-6 modulates myocardial infarction or the late phase of preconditioning (PC). Methods: Wild-type and IL-6-/- mice underwent a 30-min coronary occlusion followed by 24 h of reperfusion with or without six cycles of coronary occlusion/reperfusion 24 h earlier. Myocardial IL-6 protein expression, activation of Janus kinase (JAK) 1 and JAK2, and signal transducers and activators of transcription (STAT) 1 and STAT3 after ischemic PC protocol were examined. The expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 was determined 24 h after the PC ischemia. Results: In preconditioned wild-type mice, infarct size was reduced from 60.5±2.6% of the risk region to 33.5±3.6%, indicating a late PC effect. In nonpreconditioned IL-6-/- mice, infarct size was similar to that observed in wild-type mice (59.9±3.8%), indicating that the deletion of IL-6 has no effect on infarct size. However, in preconditioned IL-6 -/- mice, infarct size was not reduced (65.1±3.1%), indicating that the infarct-sparing effect was completely abrogated. Ischemic PC increased the expression of IL-6 in the cytoplasm of cardiomyocytes in the ischemic/reperfused zone. In IL-6-/- mice, the ischemic PC-induced activation of JAK1 and JAK2 and STAT1 and STAT3 was significantly reduced, and the increase in iNOS and COX-2 protein expression 24 h after the PC ischemia was markedly attenuated. Conclusion: IL-6 does not modulate myocardial infarct size in naïve myocardium. However, following a PC stimulus, IL-6 is obligatorily required for the activation of the JAK-STAT pathway, the ensuing upregulation of iNOS and COX-2 (co-mediators of late PC), and the development of a cardioprotective phenotype.

Original languageEnglish (US)
Pages (from-to)61-71
Number of pages11
JournalCardiovascular research
Volume64
Issue number1
DOIs
StatePublished - Oct 1 2004

Keywords

  • Cyclooxygenase
  • Infarction
  • Interleukins
  • Preconditioning
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Dawn, B., Xuan, Y. T., Guo, Y., Rezazadeh, A., Stein, A. B., Hunt, G., Wu, W. J., Tan, W., & Bolli, R. (2004). IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2. Cardiovascular research, 64(1), 61-71. https://doi.org/10.1016/j.cardiores.2004.05.011