Regulation of the SK3 channel by microRNA-499 - Potential role in atrial fibrillation

Tian You Ling, Xiao Li Wang, Qiang Chai, Tin Wah Lau, Celeste M. Koestler, Soon J. Park, Richard C. Daly, Kevin L. Greason, Jin Jen, Li Qun Wu, Wei Feng Shen, Win Kuang Shen, Yong-Mei Cha, Hon Chi Lee

Research output: Contribution to journalArticle

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Abstract

Background MicroRNAs are important regulators of gene expression, including those involving electrical remodeling in atrial fibrillation (AF). Recently, KCNN3, the gene that encodes the small-conductance calcium-activated potassium channel 3 (SK3), was found to be strongly associated with AF. Objectives To evaluate the changes in atrial myocardial microRNAs in patients with permanent AF and to determine the role of microRNA on the regulation of cardiac SK3 expression. Methods Atrial tissue obtained during cardiac surgery from patients (4 sinus rhythm and 4 permanent AF) was analyzed by using microRNA arrays. Potential targets of microRNAs were predicted by using software programs. The effects of specific microRNAs on target gene expression were evaluated in HL-1 cells from a continuously proliferating mouse hyperplastic atrial cardiomyocyte cell line. Interactions between microRNAs and targets were further evaluated by using luciferase reporter assay and by using Argonaute pull-down assay. Results Twenty-one microRNAs showed significant (>2-fold) changes in AF. MicroRNA 499 (miR-499) was upregulated by 2.33-fold (P <.01) in AF atria, whereas SK3 protein expression was downregulated by 46% (P <.05). Transfection of miR-499 mimic in HL-1 cells resulted in the downregulation of SK3 protein expression, while that of miR-499 inhibitor upregulated SK3 expression. Binding of miR-499 to the 3′ untranslated region of KCNN3 was confirmed by luciferase reporter assay and by the increased presence of SK3 mRNA in Argonaute pulled-down microRNA-induced silencing complexes after transfection with miR-499. Conclusion Atrial miR-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF.

Original languageEnglish (US)
Pages (from-to)1001-1009
Number of pages9
JournalHeart Rhythm
Volume10
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

MicroRNAs
Atrial Fibrillation
Atrial Remodeling
Down-Regulation
Luciferases
Transfection
Small-Conductance Calcium-Activated Potassium Channels
Gene Expression
3' Untranslated Regions
Regulator Genes
Cardiac Myocytes
Thoracic Surgery
Proteins
Software

Keywords

  • Atrial fibrillation
  • Electrical remodeling
  • MicroRNA
  • SK3 channel
  • Small-conductance calcium-activated potassium channel

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Ling, T. Y., Wang, X. L., Chai, Q., Lau, T. W., Koestler, C. M., Park, S. J., ... Lee, H. C. (2013). Regulation of the SK3 channel by microRNA-499 - Potential role in atrial fibrillation. Heart Rhythm, 10(7), 1001-1009. https://doi.org/10.1016/j.hrthm.2013.03.005

Regulation of the SK3 channel by microRNA-499 - Potential role in atrial fibrillation. / Ling, Tian You; Wang, Xiao Li; Chai, Qiang; Lau, Tin Wah; Koestler, Celeste M.; Park, Soon J.; Daly, Richard C.; Greason, Kevin L.; Jen, Jin; Wu, Li Qun; Shen, Wei Feng; Shen, Win Kuang; Cha, Yong-Mei; Lee, Hon Chi.

In: Heart Rhythm, Vol. 10, No. 7, 07.2013, p. 1001-1009.

Research output: Contribution to journalArticle

Ling, TY, Wang, XL, Chai, Q, Lau, TW, Koestler, CM, Park, SJ, Daly, RC, Greason, KL, Jen, J, Wu, LQ, Shen, WF, Shen, WK, Cha, Y-M & Lee, HC 2013, 'Regulation of the SK3 channel by microRNA-499 - Potential role in atrial fibrillation', Heart Rhythm, vol. 10, no. 7, pp. 1001-1009. https://doi.org/10.1016/j.hrthm.2013.03.005
Ling, Tian You ; Wang, Xiao Li ; Chai, Qiang ; Lau, Tin Wah ; Koestler, Celeste M. ; Park, Soon J. ; Daly, Richard C. ; Greason, Kevin L. ; Jen, Jin ; Wu, Li Qun ; Shen, Wei Feng ; Shen, Win Kuang ; Cha, Yong-Mei ; Lee, Hon Chi. / Regulation of the SK3 channel by microRNA-499 - Potential role in atrial fibrillation. In: Heart Rhythm. 2013 ; Vol. 10, No. 7. pp. 1001-1009.
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abstract = "Background MicroRNAs are important regulators of gene expression, including those involving electrical remodeling in atrial fibrillation (AF). Recently, KCNN3, the gene that encodes the small-conductance calcium-activated potassium channel 3 (SK3), was found to be strongly associated with AF. Objectives To evaluate the changes in atrial myocardial microRNAs in patients with permanent AF and to determine the role of microRNA on the regulation of cardiac SK3 expression. Methods Atrial tissue obtained during cardiac surgery from patients (4 sinus rhythm and 4 permanent AF) was analyzed by using microRNA arrays. Potential targets of microRNAs were predicted by using software programs. The effects of specific microRNAs on target gene expression were evaluated in HL-1 cells from a continuously proliferating mouse hyperplastic atrial cardiomyocyte cell line. Interactions between microRNAs and targets were further evaluated by using luciferase reporter assay and by using Argonaute pull-down assay. Results Twenty-one microRNAs showed significant (>2-fold) changes in AF. MicroRNA 499 (miR-499) was upregulated by 2.33-fold (P <.01) in AF atria, whereas SK3 protein expression was downregulated by 46{\%} (P <.05). Transfection of miR-499 mimic in HL-1 cells resulted in the downregulation of SK3 protein expression, while that of miR-499 inhibitor upregulated SK3 expression. Binding of miR-499 to the 3′ untranslated region of KCNN3 was confirmed by luciferase reporter assay and by the increased presence of SK3 mRNA in Argonaute pulled-down microRNA-induced silencing complexes after transfection with miR-499. Conclusion Atrial miR-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF.",
keywords = "Atrial fibrillation, Electrical remodeling, MicroRNA, SK3 channel, Small-conductance calcium-activated potassium channel",
author = "Ling, {Tian You} and Wang, {Xiao Li} and Qiang Chai and Lau, {Tin Wah} and Koestler, {Celeste M.} and Park, {Soon J.} and Daly, {Richard C.} and Greason, {Kevin L.} and Jin Jen and Wu, {Li Qun} and Shen, {Wei Feng} and Shen, {Win Kuang} and Yong-Mei Cha and Lee, {Hon Chi}",
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T1 - Regulation of the SK3 channel by microRNA-499 - Potential role in atrial fibrillation

AU - Ling, Tian You

AU - Wang, Xiao Li

AU - Chai, Qiang

AU - Lau, Tin Wah

AU - Koestler, Celeste M.

AU - Park, Soon J.

AU - Daly, Richard C.

AU - Greason, Kevin L.

AU - Jen, Jin

AU - Wu, Li Qun

AU - Shen, Wei Feng

AU - Shen, Win Kuang

AU - Cha, Yong-Mei

AU - Lee, Hon Chi

PY - 2013/7

Y1 - 2013/7

N2 - Background MicroRNAs are important regulators of gene expression, including those involving electrical remodeling in atrial fibrillation (AF). Recently, KCNN3, the gene that encodes the small-conductance calcium-activated potassium channel 3 (SK3), was found to be strongly associated with AF. Objectives To evaluate the changes in atrial myocardial microRNAs in patients with permanent AF and to determine the role of microRNA on the regulation of cardiac SK3 expression. Methods Atrial tissue obtained during cardiac surgery from patients (4 sinus rhythm and 4 permanent AF) was analyzed by using microRNA arrays. Potential targets of microRNAs were predicted by using software programs. The effects of specific microRNAs on target gene expression were evaluated in HL-1 cells from a continuously proliferating mouse hyperplastic atrial cardiomyocyte cell line. Interactions between microRNAs and targets were further evaluated by using luciferase reporter assay and by using Argonaute pull-down assay. Results Twenty-one microRNAs showed significant (>2-fold) changes in AF. MicroRNA 499 (miR-499) was upregulated by 2.33-fold (P <.01) in AF atria, whereas SK3 protein expression was downregulated by 46% (P <.05). Transfection of miR-499 mimic in HL-1 cells resulted in the downregulation of SK3 protein expression, while that of miR-499 inhibitor upregulated SK3 expression. Binding of miR-499 to the 3′ untranslated region of KCNN3 was confirmed by luciferase reporter assay and by the increased presence of SK3 mRNA in Argonaute pulled-down microRNA-induced silencing complexes after transfection with miR-499. Conclusion Atrial miR-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF.

AB - Background MicroRNAs are important regulators of gene expression, including those involving electrical remodeling in atrial fibrillation (AF). Recently, KCNN3, the gene that encodes the small-conductance calcium-activated potassium channel 3 (SK3), was found to be strongly associated with AF. Objectives To evaluate the changes in atrial myocardial microRNAs in patients with permanent AF and to determine the role of microRNA on the regulation of cardiac SK3 expression. Methods Atrial tissue obtained during cardiac surgery from patients (4 sinus rhythm and 4 permanent AF) was analyzed by using microRNA arrays. Potential targets of microRNAs were predicted by using software programs. The effects of specific microRNAs on target gene expression were evaluated in HL-1 cells from a continuously proliferating mouse hyperplastic atrial cardiomyocyte cell line. Interactions between microRNAs and targets were further evaluated by using luciferase reporter assay and by using Argonaute pull-down assay. Results Twenty-one microRNAs showed significant (>2-fold) changes in AF. MicroRNA 499 (miR-499) was upregulated by 2.33-fold (P <.01) in AF atria, whereas SK3 protein expression was downregulated by 46% (P <.05). Transfection of miR-499 mimic in HL-1 cells resulted in the downregulation of SK3 protein expression, while that of miR-499 inhibitor upregulated SK3 expression. Binding of miR-499 to the 3′ untranslated region of KCNN3 was confirmed by luciferase reporter assay and by the increased presence of SK3 mRNA in Argonaute pulled-down microRNA-induced silencing complexes after transfection with miR-499. Conclusion Atrial miR-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF.

KW - Atrial fibrillation

KW - Electrical remodeling

KW - MicroRNA

KW - SK3 channel

KW - Small-conductance calcium-activated potassium channel

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