title: High-mobility group box 1 (HMGB1) downregulates cardiac transient outward potassium current (Ito) through downregulation of Kv4.2 and Kv4.3 channel transcripts and proteins.
abstract: Transient outward potassium currents (I(to)) are major early repolarization currents in shaping cardiac action potential (AP). Downregulation of I(to) contributes to AP configuration alteration in myocardial infarction (MI) and numerous other heart diseases. High-mobility group box 1 (HMGB1), a proinflammatory cytokine, has been reported to increase dramatically in the serum of patients with MI, participating in ischemia-reperfusion injury and recovery of post-infarction failing heart. This study investigated the possible role of HMGB1 in regulating cardiac I(to) and electrical stability. HMGB1 treatment for 24h significantly inhibited the current densities of heterologously expressed Kv4.3 and Kv4.2 in COS-7 cells and native I(to) in neonatal rat ventricular myocytes (NRVMs) in a dose-dependent manner. HMGB1 decreased the mRNA and protein levels of the I(to) alpha subunits Kv4.2 and Kv4.3 channels, but not the beta subunit KChIP2 and KCNE2 in NRVMs. The receptor binding domain (150-186 amino acid residues) responsible for receptor of advanced glycation end product (RAGE) binding similarly inhibited I(to)(,) while treatment with soluble RAGE that blocks binding of ligands to cell-surface RAGE partially restored I(to) current density and Kv4 protein expressions. Box A which possesses no proinflammatory activity of HMGB1 still remained part of the I(to) suppression effect. In addition to downregulating I(to), HMGB1 modestly inhibited L-type Ca(2+) current, but not I(K1). The AP duration (APD) was slightly prolonged by HMGB1 treatment. These results collectively establish HMGB1 as a novel pathological factor downregulating I(to) partially through HMGB1-RAGE interaction, providing new insights into the potential molecular mechanisms underlying the electrical remodeling in MI.
authors.affiliation: Department of Pathophysiology, Southern Medical University, Guangzhou, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Liu
authors.forename: Jianxin
authors.initials: J
authors.lastname: Deng
authors.forename: Jia
authors.initials: J
authors.lastname: Xu
authors.forename: Haitang
authors.initials: H
authors.lastname: Wang
authors.forename: Meichun
authors.initials: M
authors.lastname: Yuan
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D004594:Electrophysiology; D024243:HMGB1 Protein / Q000502:physiology*; D011188:Potassium / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D012333:RNA, Messenger; D051672:Shal Potassium Channels; D011188:Potassium