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

doi:10.1161/CIRCRESAHA.108.171835

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

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

86 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 language	English (US)
Pages (from-to)	580-590
Number of pages	11
Journal	Circulation research
Volume	103
Issue number	6
DOIs	https://doi.org/10.1161/CIRCRESAHA.108.171835
State	Published - Sep 12 2008

Funding

Keywords

Conduction
Contraction
Gene targeting
Transcription

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology

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10.1161/CIRCRESAHA.108.171835

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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

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title = "Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects",

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.",

keywords = "Conduction, Contraction, Gene targeting, Transcription",

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

year = "2008",

month = sep,

day = "12",

doi = "10.1161/CIRCRESAHA.108.171835",

language = "English (US)",

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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

TY - JOUR

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

PY - 2008/9/12

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

Abstract

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ASJC Scopus subject areas

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