Interleukin-1{beta} Reduces L-type Ca2+ Current through Protein Kinase C Epsilon Activation in Mouse Heart [Molecular Biophysics]

June 16th, 2014 by El Khoury, N., Mathieu, S., Fiset, C.

Inflammation is now widely recognized as a key component of heart disease. Patients suffering from arrhythmias and heart failure have increased levels of tumour necrosis factor-alpha (TNFα) and interleukin-1β (IL-1β). Evidence suggests that these cytokines are important mediators of cardiac remodelling; however their effects on ion channels and arrhythmogenesis remain incompletely understood. The L-type Ca 2+ current (ICaL) is a major determinant of the plateau phase of cardiac action potential and has a critical excitation-contraction coupling role. Thus, altering its properties could have detrimental effects on cardiac electrical and contractile functions. Accordingly, the objective of this study was to elucidate the effect of TNFα and IL-1β on ICaL, while exploring the underlying regulatory mechanisms. Neonatal mouse ventricular myocytes were treated with a pathophysiological concentration (30 pg/mL) of TNFα and IL-1β for 24H. Voltage-clamp recordings showed that TNFα had no effect on ICaL whereas IL-1β decreased its current density by 36%. While both IL-1β and TNFα-treated myocytes showed significant increase in reactive oxidative species (ROS), Western blot experiments revealed that only IL-1β increased PKCϵ membrane translocation. The antioxidant N-acetyl-L-cysteine normalized ROS levels and restored ICaL density. Furthermore, the PKCϵ translocation inhibitor ϵ-V1-2 blocked the effect of IL-1β on ICaL. The reduction of ICaL by IL-1β was also seen in cultured adult ventricular myocytes. Overall, chronic IL-1β treatment decreased ICaL density in cardiomyocytes. These effects implicated ROS signalling and PKCϵ activation. These findings could contribute to explain the role of IL-1β in the development of arrhythmia and heart failure.