Interleukin-1β Reduces L-type Ca2+ Current through Protein Kinase Cε Activation in Mouse Heart

Inflammation is now widely recognized as a key component of heart disease. Patients suffering from arrhythmias and heart failure have increased levels of tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta). Evidence suggests that these cytokines are important mediators of cardiac remodeling; however, their effects on ion channels and arrhythmogenesis remain incompletely understood. The L-type Ca2+ current (I-CaL) 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 TNF alpha and IL-1 beta on I-CaL, while exploring the underlying regulatory mechanisms. Neonatal mouse ventricular myocytes were treated with a pathophysiological concentration (30 pg/ml) of TNF alpha and IL-1 beta for 24 h. Voltage-clamp recordings showed that TNF alpha had no effect on I-CaL, whereas IL-1 beta decreased the current density by 36%. Although both IL-1 beta -and TNF alpha-treated myocytes showed significant increase in reactive oxidative species (ROS), Western blot experiments revealed that only IL-1 beta increased PKC epsilon membrane translocation. The antioxidant N-acetyl-L-cysteine normalized ROS levels and restored I-CaL density. Furthermore, the PKC epsilon translocation inhibitor epsilon-V1-2 blocked the effect of IL-1 beta on I-CaL. The reduction of I-CaL by IL-1 beta was also seen in cultured adult ventricular myocytes. Overall, chronic IL-1 beta treatment decreased I-CaL density in cardiomyocytes. These effects implicated ROS signaling and PKC epsilon activation. These findings could contribute to explain the role of IL-1 beta in the development of arrhythmia and heart failure.