Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects

Laura E. Briggs, Morihiko Takeda, Adolfo E. Cuadra, Hiroko Wakimoto, Melissa H. Marks, Alexandra J. Walker, Tsugio Seki, Suk P. Oh, Jonathan T. Lu, Colin Sumners, Mohan K. Raizada, Nobuo Horikoshi, Ellen O. Weinberg, Kenji Yasui, Yasuhiro Ikeda, Kenneth R. Chien, Hideko Kasahara*

*Corresponding author for this work

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

Homeobox transcription factor Nkx2-5, highly expressed in heart, is a critical factor during early embryonic cardiac development. In this study, using tamoxifen-inducible Nkx2-5 knockout mice, we demonstrate the role of Nkx2-5 in conduction and contraction in neonates within 4 days after perinatal tamoxifen injection. Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na channel pore-forming α-subunit (Nav1.5-α), the largest ion channel in the heart responsive for rapid depolarization of the action potential, which leads to increased intracellular Ca for contraction (conduction-contraction coupling). In addition, expression of ryanodine receptor 2, through which Ca is released from sarcoplasmic reticulum, was substantially reduced in Nkx2-5 knockout mice. These results indicate that Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction.

Original languageEnglish (US)
Pages (from-to)580-590
Number of pages11
JournalCirculation research
Volume103
Issue number6
DOIs
StatePublished - Sep 12 2008

Keywords

  • Conduction
  • Contraction
  • Gene targeting
  • Transcription

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Briggs, L. E., Takeda, M., Cuadra, A. E., Wakimoto, H., Marks, M. H., Walker, A. J., Seki, T., Oh, S. P., Lu, J. T., Sumners, C., Raizada, M. K., Horikoshi, N., Weinberg, E. O., Yasui, K., Ikeda, Y., Chien, K. R., & Kasahara, H. (2008). Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects. Circulation research, 103(6), 580-590. https://doi.org/10.1161/CIRCRESAHA.108.171835