title: The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient.
abstract: Rhythmic cardiac contractions depend on the organized propagation of depolarizing and repolarizing wavefronts. Repolarization is spatially heterogeneous and depends largely on gradients of potassium currents. Gradient disruption in heart disease may underlie susceptibility to fatal arrhythmias, but it is not known how this gradient is established. We show that, in mice lacking the homeodomain transcription factor Irx5, the cardiac repolarization gradient is abolished due to increased Kv4.2 potassium-channel expression in endocardial myocardium, resulting in a selective increase of the major cardiac repolarization current, I(to,f), and increased susceptibility to arrhythmias. Myocardial Irx5 is expressed in a gradient opposite that of Kv4.2, and Irx5 represses Kv4.2 expression by recruiting mBop, a cardiac transcriptional repressor. Thus, an Irx5 repressor gradient negatively regulates potassium-channel-gene expression in the heart, forming an inverse I(to,f) gradient that ensures coordinated cardiac repolarization while also preventing arrhythmias.
authors.affiliation: Program in Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Danny L
authors.initials: DL
authors.lastname: Costantini
authors.forename: Eric P
authors.initials: EP
authors.lastname: Arruda
authors.forename: Pooja
authors.initials: P
authors.lastname: Agarwal
authors.forename: Kyoung-Han
authors.initials: KH
authors.lastname: Kim
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Melanie
authors.initials: M
authors.lastname: Lebel
authors.forename: Chi Wa
authors.initials: CW
authors.lastname: Cheng
authors.forename: Chong Y
authors.initials: CY
authors.lastname: Park
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Pierce
authors.forename: Alejandra
authors.initials: A
authors.lastname: Guerchicoff
authors.forename: Guido D
authors.initials: GD
authors.lastname: Pollevick
authors.forename: Toby Y
authors.initials: TY
authors.lastname: Chan
authors.forename: M Golam
authors.initials: MG
authors.lastname: Kabir
authors.forename: Shuk Han
authors.initials: SH
authors.lastname: Cheng
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
authors.forename: Gil J
authors.initials: GJ
authors.lastname: Gross
authors.forename: Chi-chung
authors.initials: CC
authors.lastname: Hui
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
mesh_terms: D000200:Action Potentials / Q000235:genetics* / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D003433:Crosses, Genetic; D004285:Dogs; D004562:Electrocardiography; D004594:Electrophysiology; D004699:Endocardium / Q000166:cytology / Q000502:physiology; D017930:Genes, Reporter; D006352:Heart Ventricles / Q000166:cytology; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006720:Homozygote; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000166:cytology / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011233:Precipitin Tests; D011506:Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D016276:Ventricular Function; D016277:Ventricular Function, Left / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; C501601:Irx5 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D008156:Luciferases