title: Interleukin-1β reduces L-type Ca2+ current through protein kinase Cϵ activation in mouse heart.
abstract: 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-α (TNFα) and interleukin-1β (IL-1β). 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 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 24 h. Voltage-clamp recordings showed that TNFα had no effect on ICaL, whereas IL-1β decreased the current density by 36%. Although 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 signaling and PKCϵ activation. These findings could contribute to explain the role of IL-1β in the development of arrhythmia and heart failure.
authors.affiliation: From the Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec H1T 1C8, the Department of Physiology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Nabil
authors.initials: N
authors.lastname: El Khoury
authors.affiliation: From the Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec H1T 1C8, the Faculty of Pharmacy, Université de Montréal, Montréal, Québec, and.
authors.forename: Sophie
authors.initials: S
authors.lastname: Mathieu
authors.affiliation: From the Research Center, Montreal Heart Institute, 5000 Bélanger, Montréal, Québec H1T 1C8, the Faculty of Pharmacy, Université de Montréal, Montréal, Québec, and celine.fiset@icm-mhi.org.
authors.forename: Céline
authors.initials: C
authors.lastname: Fiset
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D056966:Excitation Contraction Coupling; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000975:Antioxidants; C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D053583:Interleukin-1beta; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D051744:Protein Kinase C-epsilon; D000111:Acetylcysteine
keywords: Calcium Channel; Cardiovascular Disease; Heart Failure; Inflammation; Interleukin 1 (IL-1); Interleukin-1β; Patch Clamp Electrophysiology; Protein Kinase C (PKC); Reactive Oxygen Species (ROS); Tumor Necrosis Factor (TNF)