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Publication Detail
IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Smart N, Mojet MH, Latchman DS, Marber MS, Duchen MR, Heads RJ
  • Publication date:
    2006
  • Pagination:
    164, 177
  • Journal:
    Cardiovascular Research
  • Volume:
    69
  • Print ISSN:
    0008-6363
  • Keywords:
    10, A, ACTIVATION, amplitude, AND, BOTH, Calcium, CARDIOMYOCYTES, cell, cytokine, DYSFUNCTION, EXPRESSION, FAILURE, Fluorescence, FOR, FUNCTION, Hand, HEART, IL-6, INCREASE, INDUCTION, INHIBITION, INHIBITOR, injuries, INJURY, INNER MITOCHONDRIAL MEMBRANE, Interleukin-6, IS, ischemic, Ischemic Preconditioning, MARKER, Mechanism, MECHANISMS, MEMBRANE, METHODS, Mitochondrial, MITOCHONDRIAL FUNCTION, Mitochondrial-membrane, MODEL, Morphology, NEONATAL, NITRIC OXIDE, Nitric Oxide Synthase, NITRIC-OXIDE, OF, Other, PATHWAY, preconditioning, PROTECTION, RAT, REPERFUSION, Result, secondary, SUPPRESSION, SYNTHASE, THE
Abstract
OBJECTIVE: Interleukin-6 (IL-6) is a pro-inflammatory cytokine which is a prognostic marker associated with left ventricular contractile dysfunction and heart failure. On the other hand, IL-6 activates signalling pathways which mediate delayed ischemic preconditioning. We have therefore studied the cellular mechanisms of IL-6-induced cardioprotection. METHODS: Inducible nitric oxide synthase (iNOS) expression, cardiomyocyte calcium handling, mitochondrial energetics, and the activation of protective signalling pathways in response to IL-6 were studied in a model of simulated ischemia/reperfusion (sI/R) in isolated neonatal rat ventricular cardiomyocytes. RESULTS: Reperfusion after sI/R induced a rise in cytosolic [Ca(2+)], a loss of cell morphology and integrity, and a transient increase in mitochondrial potential (Deltapsi(m)), followed by mitochondrial swelling and collapse of Deltapsi(m). Pre-treatment of cardiomyocytes with 10 ng/ml IL-6 for 6 h, 24 h prior to sI/R prevented the secondary rise in cytosolic [Ca(2+)] and induced expression of iNOS and NO-dependent protection against sI/R injury. The protection against sI/R was concomitant with a NO-dependent reduction in the amplitude of cytosolic Ca(2+) transients. IL-6 induced an increase in inner mitochondrial membrane polarisation and increased mitochondrial Ca(2+) loading (rhod-2 fluorescence) at baseline, but prevented the reperfusion-induced changes in mitochondrial function. IL-6 pre-treatment also resulted in activation of the phosphatidylinositol (PI) 3-kinase/Akt pathway, and both iNOS induction and IL-6-dependent protection were blocked by the PI 3-kinase inhibitor wortmannin. CONCLUSION: IL-6 induces a PI 3-kinase and NO-dependent protection of cardiomyocytes, which is associated with alterations in mitochondrial Ca(2+) handling, inhibition of reperfusion-induced mitochondrial depolarisation, swelling and loss of structural integrity, and suppression of cytosolic Ca(2+) transients
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