The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient.
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.
Costantini
Danny L
DL
Program in Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Arruda
Eric P
EP
Agarwal
Pooja
P
Kim
Kyoung-Han
KH
Zhu
Yonghong
Y
Zhu
Wei
W
Lebel
Melanie
M
Cheng
Chi Wa
CW
Park
Chong Y
CY
Pierce
Stephanie A
SA
Guerchicoff
Alejandra
A
Pollevick
Guido D
GD
Chan
Toby Y
TY
Kabir
M Golam
MG
Cheng
Shuk Han
SH
Husain
Mansoor
M
Antzelevitch
Charles
C
Srivastava
Deepak
D
Gross
Gil J
GJ
Hui
Chi-chung
CC
Backx
Peter H
PH
Bruneau
Benoit G
BG
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*
D018398:Homeodomain Proteins; C501601:Irx5 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D008156:Luciferases