Open AccessInterleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation
Author(s) -
Ademuyiwa S. Aromolaran,
Ujala Srivastava,
Alessandra Alì,
Mohamed Chahine,
Deana Lazaro,
Nabil ElSherif,
Pier Leopoldo Capecchi,
Franco LaghiPasini,
Pietro Enea Lazzerini,
Mohamed Boutjdir
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0208321
Subject(s) - herg , torsades de pointes , qt interval , pharmacology , medicine , proinflammatory cytokine , long qt syndrome , repolarization , inflammation , potassium channel , electrophysiology
Increased proinflammatory interleukin-6 (IL-6) levels are associated with acquired long QT-syndrome (LQTS) in patients with systemic inflammation, leading to higher risks for life-threatening polymorphic ventricular tachycardia such as Torsades de Pointes . However, the functional and molecular mechanisms of this association are not known. In most cases of acquired LQTS, the target ion channel is the human ether-á-go-go-related gene (hERG) encoding the rapid component of the delayed rectifier K current, I Kr , which plays a critical role in cardiac repolarization. Here, we tested the hypothesis that IL-6 may cause QT prolongation by suppressing I Kr . Electrophysiological and biochemical assays were used to assess the impact of IL-6 on the functional expression of I Kr in HEK293 cells and adult guinea-pig ventricular myocytes (AGPVM). In HEK293 cells, IL-6 alone or in combination with the soluble IL-6 receptor (IL-6R), produced a significant depression of I Kr peak and tail current densities. Block of IL-6R or Janus kinase (JAK) reversed the inhibitory effects of IL-6 on I Kr . In AGPVM, IL-6 prolonged action potential duration (APD) which was further prolonged in the presence of IL-6R. Similar to heterologous cells, IL-6 reduced endogenous guinea pig ERG channel mRNA and protein expression. The data are first to demonstrate that IL-6 inhibition of I Kr and the resulting prolongation of APD is mediated via IL-6R and JAK pathway activation and forms the basis for the observed clinical QT interval prolongation. These novel findings may guide the development of targeted anti-arrhythmic therapeutic interventions in patients with LQTS and inflammatory disorders.