title: Toll-like receptor 4 activation promotes cardiac arrhythmias by decreasing the transient outward potassium current (Ito) through an IRF3-dependent and MyD88-independent pathway.
abstract: Cardiac arrhythmias are one of the main causes of death worldwide. Several studies have shown that inflammation plays a key role in different cardiac diseases and Toll-like receptors (TLRs) seem to be involved in cardiac complications. In the present study, we investigated whether the activation of TLR4 induces cardiac electrical remodeling and arrhythmias, and the signaling pathway involved in these effects. Membrane potential was recorded in Wistar rat ventricle. Ca(2+) transients, as well as the L-type Ca(2+) current (ICaL) and the transient outward K(+) current (Ito), were recorded in isolated myocytes after 24 h exposure to the TLR4 agonist, lipopolysaccharide (LPS, 1 μg/ml). TLR4 stimulation in vitro promoted a cardiac electrical remodeling that leads to action potential prolongation associated with arrhythmic events, such as delayed afterdepolarization and triggered activity. After 24 h LPS incubation, Ito amplitude, as well as Kv4.3 and KChIP2 mRNA levels were reduced. The Ito decrease by LPS was prevented by inhibition of interferon regulatory factor 3 (IRF3), but not by inhibition of interleukin-1 receptor-associated kinase 4 (IRAK4) or nuclear factor kappa B (NF-κB). Extrasystolic activity was present in 25% of the cells, but apart from that, Ca(2+) transients and ICaL were not affected by LPS; however, Na(+)/Ca(2+) exchanger (NCX) activity was apparently increased. We conclude that TLR4 activation decreased Ito, which increased AP duration via a MyD88-independent, IRF3-dependent pathway. The longer action potential, associated with enhanced Ca(2+) efflux via NCX, could explain the presence of arrhythmias in the LPS group.
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Monnerat-Cahli
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, Vitoria, Spain.
authors.forename: Hiart
authors.initials: H
authors.lastname: Alonso
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, Vitoria, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Gallego
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil.
authors.forename: Micaela Lopez
authors.initials: ML
authors.lastname: Alarcón
authors.affiliation: Centro de Engenharia Biomédica, Universidade Estadual de Campinas, Campinas, Brazil.
authors.forename: Rosana A
authors.initials: RA
authors.lastname: Bassani
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, Vitoria, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Casis
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil. Electronic address: emedei70@biof.ufrj.br.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Medei
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000276:immunology / Q000502:physiology; D011188:Potassium / Q000378:metabolism*; D017208:Rats, Wistar; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism*
chemical_list: D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D011188:Potassium
keywords: Calcium handling; Cardiac electrophysiology; Signal transduction; TLR's; Transient outward potassium current