Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice

被引：29

作者：

Breckenridge, Ross A. ^{[1
,2
]}

Zuberi, Zia ^{[2
]}

Gomes, John ^{[2
]}

Orford, Robert ^{[1
]}

Dupays, Laurent ^{[1
]}

Felkin, Leanne E. ^{[3
]}

Clark, James E. ^{[4
]}

Magee, Anthony I. ^{[6
]}

Ehler, Elisabeth ^{[5
]}

Birks, Emma J. ^{[3
,7
]}

Barton, Paul J. R. ^{[3
]}

Tinker, Andrew ^{[2
]}

Mohun, Timothy J. ^{[1
]}

机构：

[1] Natl Inst Med Res, MRC, London NW7 1AA, England

[2] UCL, Ctr Clin Pharmacol, London WC1E 6JJ, England

[3] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Harefield Heart Sci Ctr, Harefield UB9 6JH, Middx, England

[4] Kings Coll London, Div Cardiovasc, London SE1 7EH, England

[5] Kings Coll London, Randall Div Cell & Mol Biophys, London SE1 7EH, England

[6] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England

[7] Royal Brompton & Harefield NHS Trust, Harefield Hosp, Harefield UB9 6JH, Middx, England

来源：

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY | 2009年 / 47卷 / 01期

基金：

英国医学研究理事会;

关键词：

Hand1; Heart failure; Transgenic; Heart; Tet-on; Arrhythmogenesis; Connexin43; Transcription factor; VENTRICULAR ASSIST DEVICE; GAP-JUNCTION CHANNELS; NATRIURETIC PEPTIDE; GENE-EXPRESSION; SUDDEN-DEATH; HEART; CONDUCTION; CONNEXIN43; HYPERTROPHY; MYOCARDIUM;

D O I：

10.1016/j.yjmcc.2009.04.007

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Elevated levels of the cardiac transcription factor Hand I have been reported in several adult cardiac diseases but it is unclear whether this change is itself maladaptive with respect to heart function. To test this possibility, we have developed a novel, inducible transgenic system, and used it to overexpress Hand1 in adult mouse hearts. Overexpression of Hand1 in the adult mouse heart leads to mild cardiac hypertrophy and a reduction in life expectancy. Treated mice show no significant fibrosis, myocyte disarray or congestive heart failure, but have a greatly reduced threshold for induced ventricular tachycardia, indicating a predisposition to cardiac arrhythmia. Within 48 h, they show a significant loss of connexin43 protein from cardiac intercalated discs, with increased intercalated disc beta-catenin expression at protein and RNA levels. These changes are sustained during prolonged Hand1 overexpression. We propose that cardiac overexpression of Hand1 offers a useful mouse model of arrhythmogenesis and elevated HAND1 may provide one of the molecular links between the failing heart and arrhythmia. Crown Copyright (C) 2009 Published by Elsevier Inc. All rights reserved.

引用

页码：133 / 141

页数：9

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