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

被引:126
作者
Sidhu, JS
Rajawat, YS
Rami, TG
Gollob, MH
Wang, ZN
Yuan, RY
Marian, AJ
DeMayo, FJ
Weilbacher, D
Taffet, GE
Davies, JK
Carling, D
Khoury, DS
Roberts, R
机构
[1] Univ Ottawa, Inst Heart, Ottawa, ON K1Y 4W7, Canada
[2] Baylor Coll Med, Houston, TX 77030 USA
[3] Univ London Imperial Coll Sci Technol & Med, London, England
基金
英国医学研究理事会;
关键词
Wolff-Parkinson-White syndrome; genetics; tachycardia;
D O I
10.1161/01.CIR.0000151291.32974.D5
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 TGR302Q 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 . min(-1) . 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.
引用
收藏
页码:21 / 29
页数:9
相关论文
共 25 条
[1]   Transgenic mice overexpressing mutant PRKAG2 define the cause of Wolff-Parkinson-White syndrome in glycogen storage cardiomyopathy [J].
Arad, M ;
Moskowitz, IP ;
Patel, VV ;
Ahmad, F ;
Perez-Atayde, AR ;
Sawyer, DB ;
Walter, M ;
Li, GH ;
Burgon, PG ;
Maguire, CT ;
Stapleton, D ;
Schmitt, JP ;
Guo, XX ;
Pizard, A ;
Kupershmidt, S ;
Roden, DM ;
Berul, CI ;
Seidman, CE ;
Seidman, JG .
CIRCULATION, 2003, 107 (22) :2850-2856
[2]   Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy [J].
Arad, M ;
Benson, DW ;
Perez-Atayde, AR ;
McKenna, WJ ;
Sparks, EA ;
Kanter, RJ ;
McGarry, K ;
Seidman, JG ;
Seidman, CE .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 109 (03) :357-362
[3]   PAROXYSMAL ATRIAL-FIBRILLATION IN THE WOLFF-PARKINSON-WHITE SYNDROME [J].
BAUERNFEIND, RA ;
WYNDHAM, CR ;
SWIRYN, SP ;
PALILEO, EV ;
STRASBERG, B ;
LAM, W ;
WESTVEER, D ;
ROSEN, KM .
AMERICAN JOURNAL OF CARDIOLOGY, 1981, 47 (03) :562-569
[4]   In vivo cardiac electrophysiology studies in the mouse [J].
Berul, CI ;
Aronovitz, MJ ;
Wang, PJ ;
Mendelsohn, ME .
CIRCULATION, 1996, 94 (10) :2641-2648
[5]   Mutations in the γ2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy:: evidence for the central role of energy compromise in disease pathogenesis [J].
Blair, E ;
Redwood, C ;
Ashrafian, H ;
Oliveira, M ;
Broxholme, J ;
Kerr, B ;
Salmon, A ;
Östman-Smith, I ;
Watkins, H .
HUMAN MOLECULAR GENETICS, 2001, 10 (11) :1215-1220
[6]   Characterization of AMP-activated protein kinase γ-subunit isoforms and their role in AMP binding [J].
Cheung, PCF ;
Salt, IP ;
Davies, SP ;
Hardie, DG ;
Carling, D .
BIOCHEMICAL JOURNAL, 2000, 346 :659-669
[7]   Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy [J].
Crilley, JG ;
Boehm, EA ;
Blair, E ;
Rajagopalan, B ;
Blamire, AM ;
Styles, P ;
McKenna, WJ ;
Östman-Smith, I ;
Clarke, K ;
Watkins, H .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2003, 41 (10) :1776-1782
[8]   Functional analysis of mutations in the γ2 subunit of AMP-activated protein kinase associated with cardiac hypertrophy and Wolff-Parkinson-White syndrome [J].
Daniel, T ;
Carling, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (52) :51017-51024
[9]   Wolff-Parkinson-White syndrome - A genetic disease? [J].
Doevendans, PA ;
Wellens, HJ .
CIRCULATION, 2001, 104 (25) :3014-3016
[10]  
Dunnigan A., 1986, CARDIAC PREEXCITATIO, P21