[HTML][HTML] Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice

G Monnerat, ML Alarcón, LR Vasconcellos… - Nature …, 2016 - nature.com
Nature communications, 2016nature.com
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 …
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.
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