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Nat Commun. 2016 Nov 24;7:13344. doi: 10.1038/ncomms13344.

Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice.

Author information

1
Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
2
LIRS-Laboratory of Immunoreceptors and Signaling, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
3
Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
4
Center for Biomedical Engineering, University of Campinas, Campinas 13.083-970, Brazil.
5
Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, 01006 Vitoria, Spain.
6
Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn D-53127, Germany.
7
Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina.
8
FIOCANCER/ VPPLR/FIOCRUZ, FIOCRUZ-Manguinhos, Rio de Janeiro 21040-360, Brazil.
9
National Center for Structural Biology and Bioimaging-CENABIO/UFRJ, Rio de Janeiro 21941-902, Brazil.

Abstract

Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1β in DM mice. IL-1β causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity. IL-1β-induced spontaneous contractile events are associated with CaMKII oxidation and phosphorylation. We further show that DM-induced arrhythmias can be successfully treated by inhibiting the IL-1β axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1β as an inflammatory connection between metabolic dysfunction and arrhythmias in DM.

PMID:
27882934
PMCID:
PMC5123037
DOI:
10.1038/ncomms13344
[Indexed for MEDLINE]
Free PMC Article

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