© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
IL-6 plays an obligatory role in late preconditioning via JAK–STAT signaling and upregulation of iNOS and COX-2
Institute of Molecular Cardiology, Division of Cardiology, University of Louisville, Louisville, KY 40292, USA
Jewish Hospital Heart and Lung Institute, Louisville, KY 40292, USA
* Corresponding author. Institute of Molecular Cardiology, Division of Cardiology, University of Louisville, Louisville, KY 40292, USA. Tel.: +1-502-852-1837; fax: +1-502-852-6474. E-mail address: rbolli{at}louisville.edu
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.
KEYWORDS Interleukins; Preconditioning; Infarction; Signal transduction; Cyclooxygenase
Time for primary review 27 days
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