Copyright © 2005, European Society of Cardiology
IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes
aCardiovascular Division, King's College London School of Medicine, Department of Cardiology, The Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK
bDepartment of Physiology, University College London, Gower Street, London WC1E 6DB
cMedical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH
* Corresponding author. Tel.: +44 20 7188 0966; fax: +44 20 7188 0970. Email address: richard.heads{at}kcl.ac.uk
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 [Ca2+], a loss of cell morphology and integrity, and a transient increase in mitochondrial potential (
m), followed by mitochondrial swelling and collapse of 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 [Ca2+] 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 Ca2+ transients. IL-6 induced an increase in inner mitochondrial membrane polarisation and increased mitochondrial Ca2+ 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 Ca2+ handling, inhibition of reperfusion-induced mitochondrial depolarisation, swelling and loss of structural integrity, and suppression of cytosolic Ca2+ transients.
KEYWORDS Interleukins; Mitochondria; Calcium; Protein kinase; Nitric oxide
1 Present Address: Molecular Medicine Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH.
Time for primary review 15 days
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