The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient

Cell. 2005 Oct 21;123(2):347-58. doi: 10.1016/j.cell.2005.08.004.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Action Potentials / genetics*
  • Action Potentials / physiology
  • Animals
  • Blotting, Western
  • Crosses, Genetic
  • Dogs
  • Electrocardiography
  • Electrophysiology
  • Endocardium / cytology
  • Endocardium / physiology
  • Genes, Reporter
  • Heart Ventricles / cytology
  • Heterozygote
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism*
  • Homozygote
  • Immunohistochemistry
  • Luciferases / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / physiology
  • Patch-Clamp Techniques
  • Pericardium / cytology
  • Pericardium / physiology
  • Potassium Channels, Voltage-Gated / genetics
  • Potassium Channels, Voltage-Gated / metabolism
  • Potassium Channels, Voltage-Gated / physiology
  • Precipitin Tests
  • Proteins / analysis
  • RNA, Messenger / analysis
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Ventricular Function*
  • Ventricular Function, Left / physiology*

Substances

  • Homeodomain Proteins
  • Irx5 protein, mouse
  • Potassium Channels, Voltage-Gated
  • Proteins
  • RNA, Messenger
  • Transcription Factors
  • Luciferases