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Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome.

Abstract：

BACKGROUND:We identified a gene (PRKAG2) that encodes the gamma-2 regulatory subunit of AMP-activated protein kinase (AMPK) with a mutation (Arg302Gln) responsible for familial Wolff-Parkinson-White (WPW) syndrome. The human phenotype consists of ventricular preexcitation, conduction abnormalities, and cardiac hypertrophy. METHODS AND RESULTS:To elucidate the molecular basis for the phenotype, transgenic mice were generated by cardiac-restricted expression of the wild-type (TG(WT)) and mutant(TG(R302Q)) PRKAG2 gene with the cardiac-specific promoter alpha-myosin heavy chain. ECG recordings and intracardiac electrophysiology studies demonstrated the TG(R302Q) mice to have ventricular preexcitation (PR interval 10+/-2 versus 33+/-5 ms in TG(WT), P<0.05) and a prolonged QRS (20+/-5 versus 10+/-1 ms in TG(WT), P<0.05). A distinct AV accessory pathway was confirmed by electrical and pharmacological stimulation and substantiated by induction of orthodromic AV reentrant tachycardia. Enzymatic activity of AMPK in the mutant heart was significantly reduced (0.009+/-0.003 versus 0.025+/-0.001 nmol x min(-1) x g(-1) in nontransgenic mice), presumably owing to the mutation disrupting the AMP binding site. Excessive cardiac glycogen was observed. Hypertrophy was confirmed by increases in heart weight (296 versus 140 mg in TG(WT)) and ventricular wall thickness. CONCLUSIONS:We have developed a genetic animal model of WPW that expresses a mutation responsible for a familial form of WPW syndrome with a phenotype identical to that of the human, including induction of supraventricular arrhythmia. The defect is due to loss of function of AMPK. Elucidation of the molecular basis should provide insight into development of the cardiac conduction system and accessory pathways.

journal_name

Circulation

journal_title

Circulation

authors

Sidhu JS,Rajawat YS,Rami TG,Gollob MH,Wang Z,Yuan R,Marian AJ,DeMayo FJ,Weilbacher D,Taffet GE,Davies JK,Carling D,Khoury DS,Roberts R

doi

10.1161/01.CIR.0000151291.32974.D5

subject

Has Abstract

pub_date

2005-01-04 00:00:00

pages

21-9

issue

eissn

0009-7322

issn

1524-4539

pii

01.CIR.0000151291.32974.D5

journal_volume

111

pub_type

杂志文章

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Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome.