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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Action Potentials
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Animals
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Antirheumatic Agents / pharmacology
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Arrhythmias, Cardiac / etiology
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Arrhythmias, Cardiac / immunology
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Arrhythmias, Cardiac / metabolism
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Calcium / metabolism
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
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Caspase 1 / metabolism
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Diabetes Mellitus, Experimental / complications
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Diabetes Mellitus, Experimental / immunology*
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Diabetes Mellitus, Experimental / metabolism
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Inflammasomes / antagonists & inhibitors
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Interleukin 1 Receptor Antagonist Protein / pharmacology
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology*
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Interleukin-1beta / metabolism
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Macrophages / immunology*
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Mice
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Mice, Transgenic
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Myocardial Contraction
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Myocytes, Cardiac / immunology
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Myocytes, Cardiac / metabolism*
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NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
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NLR Family, Pyrin Domain-Containing 3 Protein / genetics
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NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
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Potassium / metabolism
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Receptors, Interleukin-1 / antagonists & inhibitors
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Receptors, Interleukin-1 / genetics
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Receptors, Interleukin-1 / immunology
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Tachycardia, Ventricular / etiology
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Tachycardia, Ventricular / immunology*
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Tachycardia, Ventricular / metabolism
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / immunology*
Substances
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Antirheumatic Agents
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IL1B protein, mouse
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Inflammasomes
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-1beta
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Receptors, Interleukin-1
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Tlr2 protein, mouse
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Toll-Like Receptor 2
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Casp1 protein, mouse
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Caspase 1
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Potassium
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Calcium