In calcineurin-induced cardiac hypertrophy expression of Nav1.5, Cx40 and Cx43 is reduced by different mechanisms

被引:21
作者
Bierhuizen, Marti F. A. [1 ]
Boulaksil, Mohamed [1 ,2 ]
van Stuijvenberg, Leonie [1 ]
van der Nagel, Roel [1 ]
Jansen, Anita T. [1 ]
Mutsaers, Nancy A. M. [1 ]
Yildirim, Cansu [1 ]
van Veen, Toon A. B. [1 ]
de Windt, Leon J. [1 ,2 ,3 ]
Vos, Marc A. [1 ]
van Rijen, Harold V. M. [1 ]
机构
[1] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Med Physiol, NL-3584 CM Utrecht, Netherlands
[2] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands
[3] Hubrecht Inst, Utrecht, Netherlands
关键词
calcineurin; cardiac hypertrophy; cardiac sodium channel Na(v)1.5; Cx43; Cx40; gene expression; protein expression;
D O I
10.1016/j.yjmcc.2008.06.011
中图分类号
R5 [内科学];
学科分类号
1002 [临床医学]; 100201 [内科学];
摘要
Alterations in expression levels of Na(v)1.5, Cx43 and Cx40 have been frequently reported in cardiac disease and are associated with the development of arrhythmias, but little is known about the underlying molecular mechanisms. In this study we investigated electrical conduction and expression of Na(v)1.5, Cx43 and Cx40 in hearts of transgenic mice overexpressing a constitutively active form of calcineurin (MHC-CnA). ECG recordings showed that atrial, atrioventricular and ventricular activation were significantly prolonged in MHC-CnA hearts as compared to wildtype (WT) littermates. Epicardial activation and arrhythmia susceptibility analysis revealed increased ventricular activation thresholds and arrhythmia vulnerability. Moreover, epicardial ventricular activation patterns in MHC-CnA mice were highly discontinuous with multiple areas of block. These impaired conduction properties were associated with severe reductions in Na(v)1.5, Cx43 and Cx40 protein expression in MHC-CnA hearts as visualized by immunohistochemistry and immunoblotting. Real-time RT-PCR demonstrated that the decreased protein levels for Na(v)1.5 and Cx40, but not for Cx43, were accompanied by corresponding reductions at the RNA level. Cx43 RNA isoform analysis indicated that the reduction in Cx43 protein expression is caused by a post-transcriptional mechanism rather than by RNA isoform switching. In contrast, RNA isoform analysis for Cx40 and Na(v)1.5 provided additional evidence that in calcineurin-induced hypertrophy the downregulation of these proteins originates at the transcriptional level. These results provide the molecular rationale for Na(v)1.5, Cx43 and Cx40 downregulation in this model of hypertrophy and failure and the development of the pro-arrhythmic substrate. (C) 2008 Elsevier Inc. All rights reserved.
引用
收藏
页码:373 / 384
页数:12
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