Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<)

The <i<ZFHX3</i< and <i<SCN5A</i< genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na<sup<+</sup< channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitabili...
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Autor*in:	Marcos Rubio-Alarcón [verfasserIn] Anabel Cámara-Checa [verfasserIn] María Dago [verfasserIn] Teresa Crespo-García [verfasserIn] Paloma Nieto-Marín [verfasserIn] María Marín [verfasserIn] José Luis Merino [verfasserIn] Jorge Toquero [verfasserIn] Rafael Salguero-Bodes [verfasserIn] Juan Tamargo [verfasserIn] Jorge Cebrián [verfasserIn] Eva Delpón [verfasserIn] Ricardo Caballero [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	Zfhx3 Nav1.5 Tbx5 Pitx2c cardiac

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 22(2021), 23, p 13031
Übergeordnetes Werk:	volume:22 ; year:2021 ; number:23, p 13031

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms222313031

Katalog-ID:	DOAJ060769270

Internformat


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520			\|a The <i<ZFHX3</i< and <i<SCN5A</i< genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na<sup<+</sup< channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na<sup<+</sup< current (I<sub<Na</sub<) recorded in HL-1 cardiomyocytes. <i<ZFHX3</i< mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak I<sub<Na</sub< density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; <i<n</i< ≥ 8, <i<p</i< < 0.05). Zfhx3 significantly reduced the transcriptional activity of human <i<SCN5A</i<, <i<PITX2</i<, <i<TBX5</i<, and <i<NKX25</i< minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (<i<n</i< ≥ 6, <i<p</i< < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on I<sub<Na</sub< density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits I<sub<Na</sub< as a result of a direct repressor effect on the <i<SCN5A</i< promoter, the modulation of Tbx5 increasing on the I<sub<Na</sub<, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue.
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951			\|a AR
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allfields	10.3390/ijms222313031 doi (DE-627)DOAJ060769270 (DE-599)DOAJc86ad01495e945108f38d822939ffa96 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Marcos Rubio-Alarcón verfasserin aut Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<) 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The <i<ZFHX3</i< and <i<SCN5A</i< genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na<sup<+</sup< channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na<sup<+</sup< current (I<sub<Na</sub<) recorded in HL-1 cardiomyocytes. <i<ZFHX3</i< mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak I<sub<Na</sub< density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; <i<n</i< ≥ 8, <i<p</i< < 0.05). Zfhx3 significantly reduced the transcriptional activity of human <i<SCN5A</i<, <i<PITX2</i<, <i<TBX5</i<, and <i<NKX25</i< minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (<i<n</i< ≥ 6, <i<p</i< < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on I<sub<Na</sub< density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits I<sub<Na</sub< as a result of a direct repressor effect on the <i<SCN5A</i< promoter, the modulation of Tbx5 increasing on the I<sub<Na</sub<, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue. Zfhx3 <i<SCN5A</i< Nav1.5 Tbx5 Pitx2c cardiac Biology (General) Chemistry Anabel Cámara-Checa verfasserin aut María Dago verfasserin aut Teresa Crespo-García verfasserin aut Paloma Nieto-Marín verfasserin aut María Marín verfasserin aut José Luis Merino verfasserin aut Jorge Toquero verfasserin aut Rafael Salguero-Bodes verfasserin aut Juan Tamargo verfasserin aut Jorge Cebrián verfasserin aut Eva Delpón verfasserin aut Ricardo Caballero verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 23, p 13031 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:23, p 13031 https://doi.org/10.3390/ijms222313031 kostenfrei https://doaj.org/article/c86ad01495e945108f38d822939ffa96 kostenfrei https://www.mdpi.com/1422-0067/22/23/13031 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 23, p 13031
spelling	10.3390/ijms222313031 doi (DE-627)DOAJ060769270 (DE-599)DOAJc86ad01495e945108f38d822939ffa96 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Marcos Rubio-Alarcón verfasserin aut Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<) 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The <i<ZFHX3</i< and <i<SCN5A</i< genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na<sup<+</sup< channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na<sup<+</sup< current (I<sub<Na</sub<) recorded in HL-1 cardiomyocytes. <i<ZFHX3</i< mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak I<sub<Na</sub< density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; <i<n</i< ≥ 8, <i<p</i< < 0.05). Zfhx3 significantly reduced the transcriptional activity of human <i<SCN5A</i<, <i<PITX2</i<, <i<TBX5</i<, and <i<NKX25</i< minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (<i<n</i< ≥ 6, <i<p</i< < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on I<sub<Na</sub< density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits I<sub<Na</sub< as a result of a direct repressor effect on the <i<SCN5A</i< promoter, the modulation of Tbx5 increasing on the I<sub<Na</sub<, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue. Zfhx3 <i<SCN5A</i< Nav1.5 Tbx5 Pitx2c cardiac Biology (General) Chemistry Anabel Cámara-Checa verfasserin aut María Dago verfasserin aut Teresa Crespo-García verfasserin aut Paloma Nieto-Marín verfasserin aut María Marín verfasserin aut José Luis Merino verfasserin aut Jorge Toquero verfasserin aut Rafael Salguero-Bodes verfasserin aut Juan Tamargo verfasserin aut Jorge Cebrián verfasserin aut Eva Delpón verfasserin aut Ricardo Caballero verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 23, p 13031 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:23, p 13031 https://doi.org/10.3390/ijms222313031 kostenfrei https://doaj.org/article/c86ad01495e945108f38d822939ffa96 kostenfrei https://www.mdpi.com/1422-0067/22/23/13031 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 23, p 13031
allfields_unstemmed	10.3390/ijms222313031 doi (DE-627)DOAJ060769270 (DE-599)DOAJc86ad01495e945108f38d822939ffa96 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Marcos Rubio-Alarcón verfasserin aut Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<) 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The <i<ZFHX3</i< and <i<SCN5A</i< genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na<sup<+</sup< channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na<sup<+</sup< current (I<sub<Na</sub<) recorded in HL-1 cardiomyocytes. <i<ZFHX3</i< mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak I<sub<Na</sub< density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; <i<n</i< ≥ 8, <i<p</i< < 0.05). Zfhx3 significantly reduced the transcriptional activity of human <i<SCN5A</i<, <i<PITX2</i<, <i<TBX5</i<, and <i<NKX25</i< minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (<i<n</i< ≥ 6, <i<p</i< < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on I<sub<Na</sub< density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits I<sub<Na</sub< as a result of a direct repressor effect on the <i<SCN5A</i< promoter, the modulation of Tbx5 increasing on the I<sub<Na</sub<, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue. Zfhx3 <i<SCN5A</i< Nav1.5 Tbx5 Pitx2c cardiac Biology (General) Chemistry Anabel Cámara-Checa verfasserin aut María Dago verfasserin aut Teresa Crespo-García verfasserin aut Paloma Nieto-Marín verfasserin aut María Marín verfasserin aut José Luis Merino verfasserin aut Jorge Toquero verfasserin aut Rafael Salguero-Bodes verfasserin aut Juan Tamargo verfasserin aut Jorge Cebrián verfasserin aut Eva Delpón verfasserin aut Ricardo Caballero verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 23, p 13031 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:23, p 13031 https://doi.org/10.3390/ijms222313031 kostenfrei https://doaj.org/article/c86ad01495e945108f38d822939ffa96 kostenfrei https://www.mdpi.com/1422-0067/22/23/13031 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 23, p 13031
allfieldsGer	10.3390/ijms222313031 doi (DE-627)DOAJ060769270 (DE-599)DOAJc86ad01495e945108f38d822939ffa96 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Marcos Rubio-Alarcón verfasserin aut Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<) 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The <i<ZFHX3</i< and <i<SCN5A</i< genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na<sup<+</sup< channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na<sup<+</sup< current (I<sub<Na</sub<) recorded in HL-1 cardiomyocytes. <i<ZFHX3</i< mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak I<sub<Na</sub< density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; <i<n</i< ≥ 8, <i<p</i< < 0.05). Zfhx3 significantly reduced the transcriptional activity of human <i<SCN5A</i<, <i<PITX2</i<, <i<TBX5</i<, and <i<NKX25</i< minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (<i<n</i< ≥ 6, <i<p</i< < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on I<sub<Na</sub< density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits I<sub<Na</sub< as a result of a direct repressor effect on the <i<SCN5A</i< promoter, the modulation of Tbx5 increasing on the I<sub<Na</sub<, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue. Zfhx3 <i<SCN5A</i< Nav1.5 Tbx5 Pitx2c cardiac Biology (General) Chemistry Anabel Cámara-Checa verfasserin aut María Dago verfasserin aut Teresa Crespo-García verfasserin aut Paloma Nieto-Marín verfasserin aut María Marín verfasserin aut José Luis Merino verfasserin aut Jorge Toquero verfasserin aut Rafael Salguero-Bodes verfasserin aut Juan Tamargo verfasserin aut Jorge Cebrián verfasserin aut Eva Delpón verfasserin aut Ricardo Caballero verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 23, p 13031 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:23, p 13031 https://doi.org/10.3390/ijms222313031 kostenfrei https://doaj.org/article/c86ad01495e945108f38d822939ffa96 kostenfrei https://www.mdpi.com/1422-0067/22/23/13031 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 23, p 13031
allfieldsSound	10.3390/ijms222313031 doi (DE-627)DOAJ060769270 (DE-599)DOAJc86ad01495e945108f38d822939ffa96 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Marcos Rubio-Alarcón verfasserin aut Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<) 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The <i<ZFHX3</i< and <i<SCN5A</i< genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na<sup<+</sup< channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na<sup<+</sup< current (I<sub<Na</sub<) recorded in HL-1 cardiomyocytes. <i<ZFHX3</i< mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak I<sub<Na</sub< density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; <i<n</i< ≥ 8, <i<p</i< < 0.05). Zfhx3 significantly reduced the transcriptional activity of human <i<SCN5A</i<, <i<PITX2</i<, <i<TBX5</i<, and <i<NKX25</i< minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (<i<n</i< ≥ 6, <i<p</i< < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on I<sub<Na</sub< density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits I<sub<Na</sub< as a result of a direct repressor effect on the <i<SCN5A</i< promoter, the modulation of Tbx5 increasing on the I<sub<Na</sub<, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue. Zfhx3 <i<SCN5A</i< Nav1.5 Tbx5 Pitx2c cardiac Biology (General) Chemistry Anabel Cámara-Checa verfasserin aut María Dago verfasserin aut Teresa Crespo-García verfasserin aut Paloma Nieto-Marín verfasserin aut María Marín verfasserin aut José Luis Merino verfasserin aut Jorge Toquero verfasserin aut Rafael Salguero-Bodes verfasserin aut Juan Tamargo verfasserin aut Jorge Cebrián verfasserin aut Eva Delpón verfasserin aut Ricardo Caballero verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 22(2021), 23, p 13031 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:22 year:2021 number:23, p 13031 https://doi.org/10.3390/ijms222313031 kostenfrei https://doaj.org/article/c86ad01495e945108f38d822939ffa96 kostenfrei https://www.mdpi.com/1422-0067/22/23/13031 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2021 23, p 13031
language	English
source	In International Journal of Molecular Sciences 22(2021), 23, p 13031 volume:22 year:2021 number:23, p 13031
sourceStr	In International Journal of Molecular Sciences 22(2021), 23, p 13031 volume:22 year:2021 number:23, p 13031
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Zfhx3 <i<SCN5A</i< Nav1.5 Tbx5 Pitx2c cardiac Biology (General) Chemistry
isfreeaccess_bool	true
container_title	International Journal of Molecular Sciences
authorswithroles_txt_mv	Marcos Rubio-Alarcón @@aut@@ Anabel Cámara-Checa @@aut@@ María Dago @@aut@@ Teresa Crespo-García @@aut@@ Paloma Nieto-Marín @@aut@@ María Marín @@aut@@ José Luis Merino @@aut@@ Jorge Toquero @@aut@@ Rafael Salguero-Bodes @@aut@@ Juan Tamargo @@aut@@ Jorge Cebrián @@aut@@ Eva Delpón @@aut@@ Ricardo Caballero @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	316340715
id	DOAJ060769270
language_de	englisch
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callnumber-first	Q - Science
author	Marcos Rubio-Alarcón
spellingShingle	Marcos Rubio-Alarcón misc QH301-705.5 misc QD1-999 misc Zfhx3 misc <i<SCN5A</i< misc Nav1.5 misc Tbx5 misc Pitx2c misc cardiac misc Biology (General) misc Chemistry Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<)
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topic_title	QH301-705.5 QD1-999 Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<) Zfhx3 <i<SCN5A</i< Nav1.5 Tbx5 Pitx2c cardiac
topic	misc QH301-705.5 misc QD1-999 misc Zfhx3 misc <i<SCN5A</i< misc Nav1.5 misc Tbx5 misc Pitx2c misc cardiac misc Biology (General) misc Chemistry
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title	Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<)
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title_full	Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<)
author_sort	Marcos Rubio-Alarcón
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author_browse	Marcos Rubio-Alarcón Anabel Cámara-Checa María Dago Teresa Crespo-García Paloma Nieto-Marín María Marín José Luis Merino Jorge Toquero Rafael Salguero-Bodes Juan Tamargo Jorge Cebrián Eva Delpón Ricardo Caballero
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format_se	Elektronische Aufsätze
author-letter	Marcos Rubio-Alarcón
doi_str_mv	10.3390/ijms222313031
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title_sort	zfhx3 transcription factor represses the expression of <i<scn5a</i< gene and decreases sodium current density (i<sub<na</sub<)
callnumber	QH301-705.5
title_auth	Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<)
abstract	The <i<ZFHX3</i< and <i<SCN5A</i< genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na<sup<+</sup< channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na<sup<+</sup< current (I<sub<Na</sub<) recorded in HL-1 cardiomyocytes. <i<ZFHX3</i< mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak I<sub<Na</sub< density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; <i<n</i< ≥ 8, <i<p</i< < 0.05). Zfhx3 significantly reduced the transcriptional activity of human <i<SCN5A</i<, <i<PITX2</i<, <i<TBX5</i<, and <i<NKX25</i< minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (<i<n</i< ≥ 6, <i<p</i< < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on I<sub<Na</sub< density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits I<sub<Na</sub< as a result of a direct repressor effect on the <i<SCN5A</i< promoter, the modulation of Tbx5 increasing on the I<sub<Na</sub<, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue.
abstractGer	The <i<ZFHX3</i< and <i<SCN5A</i< genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na<sup<+</sup< channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na<sup<+</sup< current (I<sub<Na</sub<) recorded in HL-1 cardiomyocytes. <i<ZFHX3</i< mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak I<sub<Na</sub< density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; <i<n</i< ≥ 8, <i<p</i< < 0.05). Zfhx3 significantly reduced the transcriptional activity of human <i<SCN5A</i<, <i<PITX2</i<, <i<TBX5</i<, and <i<NKX25</i< minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (<i<n</i< ≥ 6, <i<p</i< < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on I<sub<Na</sub< density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits I<sub<Na</sub< as a result of a direct repressor effect on the <i<SCN5A</i< promoter, the modulation of Tbx5 increasing on the I<sub<Na</sub<, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue.
abstract_unstemmed	The <i<ZFHX3</i< and <i<SCN5A</i< genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na<sup<+</sup< channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na<sup<+</sup< current (I<sub<Na</sub<) recorded in HL-1 cardiomyocytes. <i<ZFHX3</i< mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak I<sub<Na</sub< density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; <i<n</i< ≥ 8, <i<p</i< < 0.05). Zfhx3 significantly reduced the transcriptional activity of human <i<SCN5A</i<, <i<PITX2</i<, <i<TBX5</i<, and <i<NKX25</i< minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (<i<n</i< ≥ 6, <i<p</i< < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on I<sub<Na</sub< density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits I<sub<Na</sub< as a result of a direct repressor effect on the <i<SCN5A</i< promoter, the modulation of Tbx5 increasing on the I<sub<Na</sub<, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue.
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title_short	Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<)
url	https://doi.org/10.3390/ijms222313031 https://doaj.org/article/c86ad01495e945108f38d822939ffa96 https://www.mdpi.com/1422-0067/22/23/13031 https://doaj.org/toc/1661-6596 https://doaj.org/toc/1422-0067
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author2Str	Anabel Cámara-Checa María Dago Teresa Crespo-García Paloma Nieto-Marín María Marín José Luis Merino Jorge Toquero Rafael Salguero-Bodes Juan Tamargo Jorge Cebrián Eva Delpón Ricardo Caballero
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up_date	2024-07-03T16:55:11.315Z
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The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na<sup<+</sup< current (I<sub<Na</sub<) recorded in HL-1 cardiomyocytes. <i<ZFHX3</i< mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak I<sub<Na</sub< density, while the silencing of endogenous expression augmented it (from −65.9 ± 8.9 to −104.6 ± 10.8 pA/pF; <i<n</i< ≥ 8, <i<p</i< < 0.05). Zfhx3 significantly reduced the transcriptional activity of human <i<SCN5A</i<, <i<PITX2</i<, <i<TBX5</i<, and <i<NKX25</i< minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (<i<n</i< ≥ 6, <i<p</i< < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on I<sub<Na</sub< density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits I<sub<Na</sub< as a result of a direct repressor effect on the <i<SCN5A</i< promoter, the modulation of Tbx5 increasing on the I<sub<Na</sub<, and the increased expression of Nedd4-2. 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Zfhx3 Transcription Factor Represses the Expression of <i<SCN5A</i< Gene and Decreases Sodium Current Density (I<sub<Na</sub<)

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