title: Molecular Mechanisms Underlying Urate-Induced Enhancement of Kv1.5 Channel Expression in HL-1 Atrial Myocytes.
abstract: BACKGROUND
  Hyperuricemia induces endothelial dysfunction, oxidative stress and inflammation, increasing cardiovascular morbidities. It also raises the incidence of atrial fibrillation; however, underlying mechanisms are unknown.
  
  
  RESULTS
  The effects of urate on expression of Kv1.5 in cultured mouse atrial myocytes (HL-1 cells) using reverse transcriptase-PCR, immunoblots, flow cytometry and patch-clamp experiments were studied. Treatment with urate at 7 mg/dl for 24 h increased the Kv1.5 protein level, enhanced ultra-rapid delayed-rectifier K(+)channel currents and shortened action potential duration in HL-1 cells. HL-1 cells expressed the influx uric acid transporter (UAT), URATv1, and the efflux UATs, ABCG2 and MRP4. An inhibitor against URATv1, benzbromarone, abolished the urate effects, whereas an inhibitor against ABCG2, KO143, augmented them. Flow cytometry showed that urate induced an increase in reactive oxygen species, which was abolished by the antioxidant, N-acetylcysteine (NAC), and the NADPH-oxidase inhibitor, apocynin. Both NAC and apocynin abolished the enhancing effects of urate on Kv1.5 expression. A urate-induced increase in the Kv1.5 proteins was accompanied by phosphorylation of extracellular signal-regulated kinase (ERK), and was abolished by an ERK inhibitor, PD98059. NAC abolished phosphorylation of ERK by urate.
  
  
  CONCLUSIONS
  Intracellular urate taken up by UATs enhanced Kv1.5 protein expression and function in HL-1 atrial myocytes, which could be attributable to ERK phosphorylation and oxidative stress derived from nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase.
authors.affiliation: Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science.
authors.forename: Nani
authors.initials: N
authors.lastname: Maharani
authors.forename: Ya Kuang
authors.initials: YK
authors.lastname: Ting
authors.forename: Jidong
authors.initials: J
authors.lastname: Cheng
authors.forename: Akira
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Kurata
authors.forename: Peili
authors.initials: P
authors.lastname: Li
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Ikeda
authors.forename: Kumi
authors.initials: K
authors.lastname: Morikawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shirayoshi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D033461:Hyperuricemia / Q000378:metabolism* / Q000473:pathology; D051666:Kv1.5 Potassium Channel / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D014527:Uric Acid / Q000494:pharmacology*
chemical_list: D051666:Kv1.5 Potassium Channel; D009124:Muscle Proteins; D014527:Uric Acid