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

Research output: Contribution to journalArticle

61 Citations (Scopus)

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

Fingerprint

Tamoxifen
Knockout Mice
Ryanodine Receptor Calcium Release Channel
Homeobox Genes
Sarcoplasmic Reticulum
Ion Channels
Action Potentials
Embryonic Development
Transcription Factors
Injections
Genes

Keywords

  • Conduction
  • Contraction
  • Gene targeting
  • Transcription

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Briggs, L. E., Takeda, M., Cuadra, A. E., Wakimoto, H., Marks, M. H., Walker, A. J., ... 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
Briggs, Laura E. ; Takeda, Morihiko ; Cuadra, Adolfo E. ; Wakimoto, Hiroko ; Marks, Melissa H. ; Walker, Alexandra J. ; Seki, Tsugio ; Oh, Suk P. ; Lu, Jonathan T. ; Sumners, Colin ; Raizada, Mohan K. ; Horikoshi, Nobuo ; Weinberg, Ellen O. ; Yasui, Kenji ; Ikeda, Yasuhiro ; Chien, Kenneth R. ; Kasahara, Hideko. / Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects. In: Circulation Research. 2008 ; Vol. 103, No. 6. pp. 580-590.
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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.",
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Briggs, LE, Takeda, M, Cuadra, AE, Wakimoto, H, Marks, MH, Walker, AJ, Seki, T, Oh, SP, Lu, JT, Sumners, C, Raizada, MK, Horikoshi, N, Weinberg, EO, Yasui, K, Ikeda, Y, Chien, KR & Kasahara, H 2008, 'Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects' Circulation Research, vol. 103, no. 6, pp. 580-590. https://doi.org/10.1161/CIRCRESAHA.108.171835

Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects. / Briggs, Laura E.; Takeda, Morihiko; Cuadra, Adolfo E.; Wakimoto, Hiroko; Marks, Melissa H.; Walker, Alexandra J.; Seki, Tsugio; Oh, Suk P.; Lu, Jonathan T.; Sumners, Colin; Raizada, Mohan K.; Horikoshi, Nobuo; Weinberg, Ellen O.; Yasui, Kenji; Ikeda, Yasuhiro; Chien, Kenneth R.; Kasahara, Hideko.

In: Circulation Research, Vol. 103, No. 6, 12.09.2008, p. 580-590.

Research output: Contribution to journalArticle

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T1 - Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects

AU - Briggs, Laura E.

AU - Takeda, Morihiko

AU - Cuadra, Adolfo E.

AU - Wakimoto, Hiroko

AU - Marks, Melissa H.

AU - Walker, Alexandra J.

AU - Seki, Tsugio

AU - Oh, Suk P.

AU - Lu, Jonathan T.

AU - Sumners, Colin

AU - Raizada, Mohan K.

AU - Horikoshi, Nobuo

AU - Weinberg, Ellen O.

AU - Yasui, Kenji

AU - Ikeda, Yasuhiro

AU - Chien, Kenneth R.

AU - Kasahara, Hideko

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Y1 - 2008/9/12

N2 - 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.

AB - 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.

KW - Conduction

KW - Contraction

KW - Gene targeting

KW - Transcription

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Briggs LE, Takeda M, Cuadra AE, Wakimoto H, Marks MH, Walker AJ et al. Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects. Circulation Research. 2008 Sep 12;103(6):580-590. https://doi.org/10.1161/CIRCRESAHA.108.171835