Interleukin 1ß Modulates the Ventricular L-Type Calcium Current Through ROS Signalling

Abstract

Introduction & Objective: Several lines of evidence suggest that cytokines are potent mediators of cardiac remodelling including hypertrophy and generation of reactive oxidative species (ROS). Increases in serum cytokines, notably necrosis factor-alpha (TNFα) and interleukin-1β (IL-1β), have been reported in patients suffering from arrhythmias and heart failure. We previously showed that TNFα reduces the repolarizing K+ current in mice; however the effects of cytokines on other cardiac ionic currents and the mechanism by which these effects are mediated remain incompletely understood. Thus, our objective was to investigate the role of TNFα and IL-1β on L-type calcium current (ICaL), a key player in cardiomyocyte excitation-contraction coupling.Methods: Cultured neonatal mouse ventricular myocytes were treated with a pathophysiological concentration (30 pg/mL) of TNFα and IL-1β for 24H. ICaL was recorded using the voltage-clamp technique.Results: The density of ICaL (pA/pF) was decreased by 36% in IL-1β-treated myocytes compared to controls whereas TNFα had no effect. The CaV1.2 mRNA expression was unchanged by IL-1β treatment however there was a significant increase in intracelluar ROS. The antioxidant N-acetyl-L-cystein reduced ROS and restored ICaL density. Furthermore, Western blot experiments reveal that IL-1β increases PKCe membrane translocation. Treatment with a specific PKCe translocation inhibitor or pertussis toxin, the Gαi inhibitor, also reversed the effects of IL-1β.Conclusion: IL-1β significantly decreased ICaL density without affecting the expression of Cav1.2. Our results suggest that IL-1β mediates its effects by ROS signalling implicating Gαi and subsequently PKCe activation. These findings could contribute to explain the role of IL-1β in the development of arrhythmia and heart failure.