Fibroblast inward-rectifier potassium current upregulation in profibrillatory atrial Remodeling

Xiao Yan Qi, Hai Huang, Balazs Ordog, Xiaobin Luo, Patrice Naud, Yiguo Sun, Chia Tung Wu, Kristin Dawson, Artavazd Tadevosyan, Yu Chen, Masahide Harada, Dobromir Dobrev, Stanley Nattel

Research output: Contribution to journalArticle

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Abstract

Rationale: Fibroblasts are involved in cardiac arrhythmogenesis and contribute to the atrial fibrillation substrate in congestive heart failure (CHF) by generating tissue fibrosis. Fibroblasts display robust ion currents, but their functional importance is poorly understood. Objective: To characterize atrial fibroblast inward-rectifier K+ current (IK1) remodeling in CHF and its effects on fibroblast properties. Methods and Results: Freshly isolated left atrial fibroblasts were obtained from controls and dogs with CHF (ventricular tachypacing). Patch clamp was used to record resting membrane potential (RMP) and IK1. RMP was significantly increased by CHF (from -43.2±0.8 mV, control, to -55.5±0.9 mV). CHF upregulated IK1 (eg, at -90 mV from -1.1±0.2 to -2.7±0.5 pA/pF) and increased the expression of KCNJ2 mRNA (by 52%) and protein (by 80%). Ba2+ (300 μmol/L) decreased the RMP and suppressed the RMP difference between controls and dogs with CHF. Store-operated Ca2+ entry (Fura-2-acetoxymethyl ester) and fibroblast proliferation (flow cytometry) were enhanced by CHF. Lentivirus-mediated overexpression of KCNJ2 enhanced IK1 and hyperpolarized fibroblasts. Functional KCNJ2 suppression by lentivirus-mediated expression of a dominant negative KCNJ2 construct suppressed IK1 and depolarized RMP. Overexpression of KCNJ2 increased Ca2+ entry and fibroblast proliferation, whereas the dominant negative KCNJ2 construct had opposite effects. Fibroblast hyperpolarization to mimic CHF effects on RMP enhanced the Ca2+ entry. MicroRNA-26a, which targets KCNJ2, was downregulated in CHF fibroblasts. Knockdown of endogenous microRNA-26 to mimic CHF effects unregulated IK1. Conclusions: CHF upregulates fibroblast KCNJ2 expression and currents, thereby hyperpolarizing RMP, increasing Ca2+ entry, and enhancing atrial fibroblast proliferation. These effects are likely mediated by microRNA-26a downregulation. Remodeling-induced fibroblast KCNJ2 expression changes may play a role in atrial fibrillation promoting fibroblast remodeling and structural/arrhythmic consequences.

Original languageEnglish
Pages (from-to)836-845
Number of pages10
JournalCirculation Research
Volume116
Issue number5
DOIs
Publication statusPublished - 27-02-2015

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Atrial Remodeling
Potassium
Up-Regulation
Fibroblasts
Heart Failure
Membrane Potentials
MicroRNAs
Lentivirus
Atrial Fibrillation
Down-Regulation
Dogs
Fura-2

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Qi, Xiao Yan ; Huang, Hai ; Ordog, Balazs ; Luo, Xiaobin ; Naud, Patrice ; Sun, Yiguo ; Wu, Chia Tung ; Dawson, Kristin ; Tadevosyan, Artavazd ; Chen, Yu ; Harada, Masahide ; Dobrev, Dobromir ; Nattel, Stanley. / Fibroblast inward-rectifier potassium current upregulation in profibrillatory atrial Remodeling. In: Circulation Research. 2015 ; Vol. 116, No. 5. pp. 836-845.
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title = "Fibroblast inward-rectifier potassium current upregulation in profibrillatory atrial Remodeling",
abstract = "Rationale: Fibroblasts are involved in cardiac arrhythmogenesis and contribute to the atrial fibrillation substrate in congestive heart failure (CHF) by generating tissue fibrosis. Fibroblasts display robust ion currents, but their functional importance is poorly understood. Objective: To characterize atrial fibroblast inward-rectifier K+ current (IK1) remodeling in CHF and its effects on fibroblast properties. Methods and Results: Freshly isolated left atrial fibroblasts were obtained from controls and dogs with CHF (ventricular tachypacing). Patch clamp was used to record resting membrane potential (RMP) and IK1. RMP was significantly increased by CHF (from -43.2±0.8 mV, control, to -55.5±0.9 mV). CHF upregulated IK1 (eg, at -90 mV from -1.1±0.2 to -2.7±0.5 pA/pF) and increased the expression of KCNJ2 mRNA (by 52{\%}) and protein (by 80{\%}). Ba2+ (300 μmol/L) decreased the RMP and suppressed the RMP difference between controls and dogs with CHF. Store-operated Ca2+ entry (Fura-2-acetoxymethyl ester) and fibroblast proliferation (flow cytometry) were enhanced by CHF. Lentivirus-mediated overexpression of KCNJ2 enhanced IK1 and hyperpolarized fibroblasts. Functional KCNJ2 suppression by lentivirus-mediated expression of a dominant negative KCNJ2 construct suppressed IK1 and depolarized RMP. Overexpression of KCNJ2 increased Ca2+ entry and fibroblast proliferation, whereas the dominant negative KCNJ2 construct had opposite effects. Fibroblast hyperpolarization to mimic CHF effects on RMP enhanced the Ca2+ entry. MicroRNA-26a, which targets KCNJ2, was downregulated in CHF fibroblasts. Knockdown of endogenous microRNA-26 to mimic CHF effects unregulated IK1. Conclusions: CHF upregulates fibroblast KCNJ2 expression and currents, thereby hyperpolarizing RMP, increasing Ca2+ entry, and enhancing atrial fibroblast proliferation. These effects are likely mediated by microRNA-26a downregulation. Remodeling-induced fibroblast KCNJ2 expression changes may play a role in atrial fibrillation promoting fibroblast remodeling and structural/arrhythmic consequences.",
author = "Qi, {Xiao Yan} and Hai Huang and Balazs Ordog and Xiaobin Luo and Patrice Naud and Yiguo Sun and Wu, {Chia Tung} and Kristin Dawson and Artavazd Tadevosyan and Yu Chen and Masahide Harada and Dobromir Dobrev and Stanley Nattel",
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Qi, XY, Huang, H, Ordog, B, Luo, X, Naud, P, Sun, Y, Wu, CT, Dawson, K, Tadevosyan, A, Chen, Y, Harada, M, Dobrev, D & Nattel, S 2015, 'Fibroblast inward-rectifier potassium current upregulation in profibrillatory atrial Remodeling', Circulation Research, vol. 116, no. 5, pp. 836-845. https://doi.org/10.1161/CIRCRESAHA.116.305326

Fibroblast inward-rectifier potassium current upregulation in profibrillatory atrial Remodeling. / Qi, Xiao Yan; Huang, Hai; Ordog, Balazs; Luo, Xiaobin; Naud, Patrice; Sun, Yiguo; Wu, Chia Tung; Dawson, Kristin; Tadevosyan, Artavazd; Chen, Yu; Harada, Masahide; Dobrev, Dobromir; Nattel, Stanley.

In: Circulation Research, Vol. 116, No. 5, 27.02.2015, p. 836-845.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fibroblast inward-rectifier potassium current upregulation in profibrillatory atrial Remodeling

AU - Qi, Xiao Yan

AU - Huang, Hai

AU - Ordog, Balazs

AU - Luo, Xiaobin

AU - Naud, Patrice

AU - Sun, Yiguo

AU - Wu, Chia Tung

AU - Dawson, Kristin

AU - Tadevosyan, Artavazd

AU - Chen, Yu

AU - Harada, Masahide

AU - Dobrev, Dobromir

AU - Nattel, Stanley

PY - 2015/2/27

Y1 - 2015/2/27

N2 - Rationale: Fibroblasts are involved in cardiac arrhythmogenesis and contribute to the atrial fibrillation substrate in congestive heart failure (CHF) by generating tissue fibrosis. Fibroblasts display robust ion currents, but their functional importance is poorly understood. Objective: To characterize atrial fibroblast inward-rectifier K+ current (IK1) remodeling in CHF and its effects on fibroblast properties. Methods and Results: Freshly isolated left atrial fibroblasts were obtained from controls and dogs with CHF (ventricular tachypacing). Patch clamp was used to record resting membrane potential (RMP) and IK1. RMP was significantly increased by CHF (from -43.2±0.8 mV, control, to -55.5±0.9 mV). CHF upregulated IK1 (eg, at -90 mV from -1.1±0.2 to -2.7±0.5 pA/pF) and increased the expression of KCNJ2 mRNA (by 52%) and protein (by 80%). Ba2+ (300 μmol/L) decreased the RMP and suppressed the RMP difference between controls and dogs with CHF. Store-operated Ca2+ entry (Fura-2-acetoxymethyl ester) and fibroblast proliferation (flow cytometry) were enhanced by CHF. Lentivirus-mediated overexpression of KCNJ2 enhanced IK1 and hyperpolarized fibroblasts. Functional KCNJ2 suppression by lentivirus-mediated expression of a dominant negative KCNJ2 construct suppressed IK1 and depolarized RMP. Overexpression of KCNJ2 increased Ca2+ entry and fibroblast proliferation, whereas the dominant negative KCNJ2 construct had opposite effects. Fibroblast hyperpolarization to mimic CHF effects on RMP enhanced the Ca2+ entry. MicroRNA-26a, which targets KCNJ2, was downregulated in CHF fibroblasts. Knockdown of endogenous microRNA-26 to mimic CHF effects unregulated IK1. Conclusions: CHF upregulates fibroblast KCNJ2 expression and currents, thereby hyperpolarizing RMP, increasing Ca2+ entry, and enhancing atrial fibroblast proliferation. These effects are likely mediated by microRNA-26a downregulation. Remodeling-induced fibroblast KCNJ2 expression changes may play a role in atrial fibrillation promoting fibroblast remodeling and structural/arrhythmic consequences.

AB - Rationale: Fibroblasts are involved in cardiac arrhythmogenesis and contribute to the atrial fibrillation substrate in congestive heart failure (CHF) by generating tissue fibrosis. Fibroblasts display robust ion currents, but their functional importance is poorly understood. Objective: To characterize atrial fibroblast inward-rectifier K+ current (IK1) remodeling in CHF and its effects on fibroblast properties. Methods and Results: Freshly isolated left atrial fibroblasts were obtained from controls and dogs with CHF (ventricular tachypacing). Patch clamp was used to record resting membrane potential (RMP) and IK1. RMP was significantly increased by CHF (from -43.2±0.8 mV, control, to -55.5±0.9 mV). CHF upregulated IK1 (eg, at -90 mV from -1.1±0.2 to -2.7±0.5 pA/pF) and increased the expression of KCNJ2 mRNA (by 52%) and protein (by 80%). Ba2+ (300 μmol/L) decreased the RMP and suppressed the RMP difference between controls and dogs with CHF. Store-operated Ca2+ entry (Fura-2-acetoxymethyl ester) and fibroblast proliferation (flow cytometry) were enhanced by CHF. Lentivirus-mediated overexpression of KCNJ2 enhanced IK1 and hyperpolarized fibroblasts. Functional KCNJ2 suppression by lentivirus-mediated expression of a dominant negative KCNJ2 construct suppressed IK1 and depolarized RMP. Overexpression of KCNJ2 increased Ca2+ entry and fibroblast proliferation, whereas the dominant negative KCNJ2 construct had opposite effects. Fibroblast hyperpolarization to mimic CHF effects on RMP enhanced the Ca2+ entry. MicroRNA-26a, which targets KCNJ2, was downregulated in CHF fibroblasts. Knockdown of endogenous microRNA-26 to mimic CHF effects unregulated IK1. Conclusions: CHF upregulates fibroblast KCNJ2 expression and currents, thereby hyperpolarizing RMP, increasing Ca2+ entry, and enhancing atrial fibroblast proliferation. These effects are likely mediated by microRNA-26a downregulation. Remodeling-induced fibroblast KCNJ2 expression changes may play a role in atrial fibrillation promoting fibroblast remodeling and structural/arrhythmic consequences.

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