Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice.
Gustavo MonneratMicaela L AlarcónLuiz R VasconcellosCamila Hochman-MendezGuilherme Visconde BrasilRosana A BassaniOscar CasisDaniela MalanLeonardo H TravassosMarisa SepúlvedaJuan Ignacio BurgosMartin Vila-PetroffFabiano F DutraMarcelo T BozzaClaudia N PaivaAdriana Bastos CarvalhoAdriana BonomoBernd K FleischmannAntonio Carlos Campos de CarvalhoEmiliano MedeiPublished in: Nature communications (2016)
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.
Keyphrases
- nlrp inflammasome
- toll like receptor
- high glucose
- inflammatory response
- diabetic rats
- immune response
- left ventricular
- nuclear factor
- type diabetes
- drug induced
- adipose tissue
- glycemic control
- heart failure
- nitric oxide
- hydrogen peroxide
- endothelial cells
- atrial fibrillation
- insulin resistance
- smooth muscle
- stress induced
- wild type