Increased late sodium currents are related to transcription of neuronal isoforms in a pressure-overload model

Yutao Xi, Geru Wu, Lin Yang, Ke Han, Yuan Du, Tingzhong Wang, Xinjun Lei, Xiaojun Bai, Aiqun Ma

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

AimsThe late and persistent sodium current (INa) has been identified as a target for anti-arrhythmia drugs in patients with heart failure (HF). However, the underlying mechanism of late INa (INaL) production remains uncertain. We hypothesized that transcriptional alteration among sodium channel (NaCh) isoforms may contribute to INaL in failing cardiomyocytes.Methods and resultsPressure-overload rat models were created by 16-week constriction of the ascending aorta (HF). Haemodynamic and electrocardiographic variables were studied in sham operation and HF rats. Action potential (AP) and INa were recorded using whole-cell patch-clamp techniques. The expression of various NaCh isoforms was evaluated by immunocytochemistry, RT-PCR, and western blot. The HF group exhibited left ventricular enlargement, systolic dysfunction, and prolongation of QTc intervals (P < 0.05). Current-clamp recording indicated that AP durations (APDs) were more sensitive to tetrodotoxin. Voltage-clamp recordings showed that INaL was increased (-1.54 ± 0.43 vs. -1.08 ± 0.38 pA/pF, P < 0.01) in HF, but transient INa (INaT) density was decreased (-14.61 ± 2.30 vs. -26.15 ± 5.17 pA/pF, P < 0.01). Correspondingly, the relative mRNA levels of the neuronal isoforms SCN1a and SCN8a increased 2.5- and 2.7-fold, respectively; SCN3a did not change, whereas SCN5a decreased by ∼60 in HF. Protein levels paralleled their mRNA expression.ConclusionThe up-regulated expression of the neuronal NaCh isoforms SCN1a and SCN8a could be one mechanism of INaL production, which may contribute to prolongation of APD in the failing heart.

Original languageEnglish (US)
Pages (from-to)749-757
Number of pages9
JournalEuropean Journal of Heart Failure
Volume11
Issue number8
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

Fingerprint

Protein Isoforms
Heart Failure
Sodium
Pressure
Action Potentials
Messenger RNA
Sodium Channels
Anti-Arrhythmia Agents
Tetrodotoxin
Patch-Clamp Techniques
Cardiac Myocytes
Constriction
Aorta
Hemodynamics
Western Blotting
Immunohistochemistry
Polymerase Chain Reaction
Proteins

Keywords

  • Heart failure
  • Late sodium current
  • Neuronal sodium channel
  • Pressure-overload
  • Sodium channel

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Increased late sodium currents are related to transcription of neuronal isoforms in a pressure-overload model. / Xi, Yutao; Wu, Geru; Yang, Lin; Han, Ke; Du, Yuan; Wang, Tingzhong; Lei, Xinjun; Bai, Xiaojun; Ma, Aiqun.

In: European Journal of Heart Failure, Vol. 11, No. 8, 01.01.2009, p. 749-757.

Research output: Contribution to journalArticle

Xi, Yutao ; Wu, Geru ; Yang, Lin ; Han, Ke ; Du, Yuan ; Wang, Tingzhong ; Lei, Xinjun ; Bai, Xiaojun ; Ma, Aiqun. / Increased late sodium currents are related to transcription of neuronal isoforms in a pressure-overload model. In: European Journal of Heart Failure. 2009 ; Vol. 11, No. 8. pp. 749-757.
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abstract = "AimsThe late and persistent sodium current (INa) has been identified as a target for anti-arrhythmia drugs in patients with heart failure (HF). However, the underlying mechanism of late INa (INaL) production remains uncertain. We hypothesized that transcriptional alteration among sodium channel (NaCh) isoforms may contribute to INaL in failing cardiomyocytes.Methods and resultsPressure-overload rat models were created by 16-week constriction of the ascending aorta (HF). Haemodynamic and electrocardiographic variables were studied in sham operation and HF rats. Action potential (AP) and INa were recorded using whole-cell patch-clamp techniques. The expression of various NaCh isoforms was evaluated by immunocytochemistry, RT-PCR, and western blot. The HF group exhibited left ventricular enlargement, systolic dysfunction, and prolongation of QTc intervals (P < 0.05). Current-clamp recording indicated that AP durations (APDs) were more sensitive to tetrodotoxin. Voltage-clamp recordings showed that INaL was increased (-1.54 ± 0.43 vs. -1.08 ± 0.38 pA/pF, P < 0.01) in HF, but transient INa (INaT) density was decreased (-14.61 ± 2.30 vs. -26.15 ± 5.17 pA/pF, P < 0.01). Correspondingly, the relative mRNA levels of the neuronal isoforms SCN1a and SCN8a increased 2.5- and 2.7-fold, respectively; SCN3a did not change, whereas SCN5a decreased by ∼60 in HF. Protein levels paralleled their mRNA expression.ConclusionThe up-regulated expression of the neuronal NaCh isoforms SCN1a and SCN8a could be one mechanism of INaL production, which may contribute to prolongation of APD in the failing heart.",
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T1 - Increased late sodium currents are related to transcription of neuronal isoforms in a pressure-overload model

AU - Xi, Yutao

AU - Wu, Geru

AU - Yang, Lin

AU - Han, Ke

AU - Du, Yuan

AU - Wang, Tingzhong

AU - Lei, Xinjun

AU - Bai, Xiaojun

AU - Ma, Aiqun

PY - 2009/1/1

Y1 - 2009/1/1

N2 - AimsThe late and persistent sodium current (INa) has been identified as a target for anti-arrhythmia drugs in patients with heart failure (HF). However, the underlying mechanism of late INa (INaL) production remains uncertain. We hypothesized that transcriptional alteration among sodium channel (NaCh) isoforms may contribute to INaL in failing cardiomyocytes.Methods and resultsPressure-overload rat models were created by 16-week constriction of the ascending aorta (HF). Haemodynamic and electrocardiographic variables were studied in sham operation and HF rats. Action potential (AP) and INa were recorded using whole-cell patch-clamp techniques. The expression of various NaCh isoforms was evaluated by immunocytochemistry, RT-PCR, and western blot. The HF group exhibited left ventricular enlargement, systolic dysfunction, and prolongation of QTc intervals (P < 0.05). Current-clamp recording indicated that AP durations (APDs) were more sensitive to tetrodotoxin. Voltage-clamp recordings showed that INaL was increased (-1.54 ± 0.43 vs. -1.08 ± 0.38 pA/pF, P < 0.01) in HF, but transient INa (INaT) density was decreased (-14.61 ± 2.30 vs. -26.15 ± 5.17 pA/pF, P < 0.01). Correspondingly, the relative mRNA levels of the neuronal isoforms SCN1a and SCN8a increased 2.5- and 2.7-fold, respectively; SCN3a did not change, whereas SCN5a decreased by ∼60 in HF. Protein levels paralleled their mRNA expression.ConclusionThe up-regulated expression of the neuronal NaCh isoforms SCN1a and SCN8a could be one mechanism of INaL production, which may contribute to prolongation of APD in the failing heart.

AB - AimsThe late and persistent sodium current (INa) has been identified as a target for anti-arrhythmia drugs in patients with heart failure (HF). However, the underlying mechanism of late INa (INaL) production remains uncertain. We hypothesized that transcriptional alteration among sodium channel (NaCh) isoforms may contribute to INaL in failing cardiomyocytes.Methods and resultsPressure-overload rat models were created by 16-week constriction of the ascending aorta (HF). Haemodynamic and electrocardiographic variables were studied in sham operation and HF rats. Action potential (AP) and INa were recorded using whole-cell patch-clamp techniques. The expression of various NaCh isoforms was evaluated by immunocytochemistry, RT-PCR, and western blot. The HF group exhibited left ventricular enlargement, systolic dysfunction, and prolongation of QTc intervals (P < 0.05). Current-clamp recording indicated that AP durations (APDs) were more sensitive to tetrodotoxin. Voltage-clamp recordings showed that INaL was increased (-1.54 ± 0.43 vs. -1.08 ± 0.38 pA/pF, P < 0.01) in HF, but transient INa (INaT) density was decreased (-14.61 ± 2.30 vs. -26.15 ± 5.17 pA/pF, P < 0.01). Correspondingly, the relative mRNA levels of the neuronal isoforms SCN1a and SCN8a increased 2.5- and 2.7-fold, respectively; SCN3a did not change, whereas SCN5a decreased by ∼60 in HF. Protein levels paralleled their mRNA expression.ConclusionThe up-regulated expression of the neuronal NaCh isoforms SCN1a and SCN8a could be one mechanism of INaL production, which may contribute to prolongation of APD in the failing heart.

KW - Heart failure

KW - Late sodium current

KW - Neuronal sodium channel

KW - Pressure-overload

KW - Sodium channel

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