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European Journal of Heart Failure Advance Access originally published online on July 7, 2009
European Journal of Heart Failure 2009 11(8):749-757; doi:10.1093/eurjhf/hfp092
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

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

Yutao Xi1,2,*, Geru Wu1,2, Lin Yang1,2, Ke Han1,2, Yuan Du1,2, Tingzhong Wang1,2, Xinjun Lei1,2, Xiaojun Bai1,2 and Aiqun Ma1,2,*

1 Department of Cardiovascular Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, China
2 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, China

* Corresponding author. Tel/Fax: +86 2985261809, Email: maaiqun{at}medmail.com.cn (A.M.) or xirainwave{at}hotmail.com (Y.X.)


  Abstract

Aims: The 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 results: Pressure-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.

Conclusion: The 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.

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

Received December 21, 2008; Revised April 21, 2009; Accepted May 14, 2009


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