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Receptor activator of nuclear factor-κB ligand is a novel inducer of myocardial inflammation

Title
Receptor activator of nuclear factor-κB ligand is a novel inducer of myocardial inflammation
Authors
Ock S.Ahn J.Lee S.H.Park H.Son J.W.Oh J.G.Yang D.K.Lee W.S.Kim H.-S.Rho J.Oh G.T.Abel E.D.Park W.J.Min J.-K.Kim J.
Ewha Authors
오구택
SCOPUS Author ID
오구택scopus
Issue Date
2012
Journal Title
Cardiovascular Research
ISSN
0008-6363JCR Link
Citation
vol. 94, no. 1, pp. 105 - 114
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Aims: Although increased levels of myocardial receptor activator of nuclear factor (NF)-κB ligand (RANKL) have been reported in heart failure, the role of this pathway in mediating activation of inflammatory pathways during myocardial remodelling is less well understood. This study sought to determine the role of myocardial RANKL in regulating cytokine expression. Methods and results: A marked increase in RANKL expression occurred as early as 6h following transverse aortic constriction (TAC) in mouse hearts and persisted at 3 and 17 days. An increase in tumour necrosis factor-α (TNF-α), interleukin (IL)-1α, and IL-1β was observed in the hypertrophied hearts only at 3 or 17 days after TAC. Treatment with losartan significantly attenuated TAC-induced cardiac hypertrophy, in parallel with decreased expression of RANKL, TNF-α, IL-1α, and IL-1β. Furthermore, injection of a RANKL-neutralizing monoclonal antibody attenuated RANKL-induced cytokine expression. RANKL stimulated expression of TNF-α, IL-1α, and IL-1β in neonatal rat cardiomyocytes via activation of NF-κB. RANKL-induced NF-κB activation and expression of these cytokines were both attenuated when RANK, receptor for RANKL, or TRAF2 or TRAF6, adaptors for RANK, was silenced by siRNA. Furthermore, inhibitors of phospholipase C (PLC), protein kinase C (PKC), and inhibitor of κB kinase also significantly inhibited RANKL-induced cellular activities, but inhibitors of phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, or p38 mitogen-activated protein kinase were without effect. Conclusion: Our data demonstrate for the first time that the pressure-overloaded myocardium generates RANKL, which induces TNF-α, IL-1α, and IL-1β production via a RANKTRAF2/TRAF6PLCPKCNF-κB-mediated autocrine mechanism. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012.
DOI
10.1093/cvr/cvs078
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자연과학대학 > 생명과학전공 > Journal papers
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