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Treatment with anti-RANKL antibody reduces infarct size and attenuates dysfunction impacting on neutrophil-mediated injury

Crowe, Lindsey A
Brandt, Karim J
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Published in Journal of Molecular and Cellular Cardiology. 2016, vol. 94, p. 82-94
Abstract Selective pharmacological treatments targeting reperfusion injury produced modest protective effects and might be associated with immunosuppression. In order to identify novel and better-tolerated approaches, we focused on the neutralization of receptor activator of nuclear factor kappa-B ligand [RANKL], a cytokine recently shown to activate inflammatory cells (i.e. neutrophils) orchestrating post-infarction injury and repair. Myocardial ischemia (60min) and reperfusion injury was surgically induced in C57Bl/6 mice. In hearts and serum, RANKL was early upregulated during reperfusion. A "one-shot" injection with neutralizing anti-RANKL IgG during ischemia ameliorated myocardial infarct size and function, but not adverse remodeling (determined by Magnetic Resonance Imaging [MRI]) as compared to Vehicle or control IgG. These beneficial effects were accompanied in vivo by reduction in cardiac neutrophil infiltration, reactive oxygen species (ROS) and MMP-9 release. Anti-RANKL IgG treatment suppressed sudden peak of neutrophil granule products in mouse serum early after reperfusion onset. In vitro, RANK mRNA expression was detected in isolated mouse neutrophils. Co-incubation with neutralizing anti-RANKL IgG abrogated RANKL-induced mouse neutrophil degranulation and migration, suggesting a critical role of RANKL in neutrophil-mediated injury. Conversely, anti-RANKL IgG did not affect salvage pathways in cardiac cells (i.e. ERK p42/p44, Akt and STAT-3) or macrophage cardiac infiltration. Finally, treatment with anti-RANKL IgG showed no effect on B and T lymphocyte polarization (in serum, spleen and infarcted myocardium) and circulating chemokines as compared with Vehicle or control IgG. In conclusion, acute treatment with anti-RANKL IgG improved cardiac infarct size and function by potentially impacting on neutrophil-mediated injury and repair.
Keywords Myocardial infarctionInflammationNeutrophils
PMID: 27056420
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Article (Accepted version) (2 MB) - document accessible for UNIGE members only Limited access to UNIGE
Research groups Groupe Roth Arnaud (oncologie) (285)
Imagerie cardiaque fonctionnelle (541)
L'athérosclérose et ses complications cliniques (591)
Métastases du foie (657)
Traits génétiques complexes (901)
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CARBONE, Federico et al. Treatment with anti-RANKL antibody reduces infarct size and attenuates dysfunction impacting on neutrophil-mediated injury. In: Journal of Molecular and Cellular Cardiology, 2016, vol. 94, p. 82-94. doi: 10.1016/j.yjmcc.2016.03.013 https://archive-ouverte.unige.ch/unige:84747

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Deposited on : 2016-06-27

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