ParkinsonCanadaV1, PascalFrancis, Corpus, bibRecord, 000924

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

Identifieur interne : 000924 ( PascalFrancis/Corpus ); précédent : 000923; suivant : 000925

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

Auteurs : Jasvinder S. Sidhu ; Yadavendra S. Rajawat ; Tapan G. Rami ; Michael H. Gollob ; ZHINONG WANG ; RUIYONG YUAN ; A. J. Marian ; Francesco J. Demayo ; Donald Weilbacher ; George E. Taffet ; Joanna K. Davies ; David Carling ; Dirar S. Khoury ; Robert Roberts

Source :

Circulation : (New York, N.Y.) [ 0009-7322 ] ; 2005.

RBID : Pascal:05-0173141

Descripteurs français

Pascal (Inist)
- Appareil circulatoire pathologie, Animal, Souris, Tachycardie ventriculaire, AMP, Protein kinase, Wolff Parkinson White syndrome, Mutation.

English descriptors

KwdEn :
- AMP, Animal, Cardiovascular disease, Mouse, Mutation, Protein kinase, Ventricular tachycardia, Wolff Parkinson White syndrome.

Abstract

Background-We identified a gene (PRKAG2) that encodes the γ-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 α-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 . 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.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

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A08	`01`	`1`	`ENG`	`@1 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`
A11	`01`	`1`		`@1 SIDHU (Jasvinder S.)`
A11	`02`	`1`		`@1 RAJAWAT (Yadavendra S.)`
A11	`03`	`1`		`@1 RAMI (Tapan G.)`
A11	`04`	`1`		`@1 GOLLOB (Michael H.)`
A11	`05`	`1`		`@1 ZHINONG WANG`
A11	`06`	`1`		`@1 RUIYONG YUAN`
A11	`07`	`1`		`@1 MARIAN (A. J.)`
A11	`08`	`1`		`@1 DEMAYO (Francesco J.)`
A11	`09`	`1`		`@1 WEILBACHER (Donald)`
A11	`10`	`1`		`@1 TAFFET (George E.)`
A11	`11`	`1`		`@1 DAVIES (Joanna K.)`
A11	`12`	`1`		`@1 CARLING (David)`
A11	`13`	`1`		`@1 KHOURY (Dirar S.)`
A11	`14`	`1`		`@1 ROBERTS (Robert)`
A14	`01`			`@1 Baylor College of Medicine @2 Houston, Tex @3 USA @Z 1 aut. @Z 2 aut. @Z 3 aut. @Z 5 aut. @Z 6 aut. @Z 7 aut. @Z 8 aut. @Z 9 aut. @Z 10 aut. @Z 13 aut.`
A14	`02`			`@1 University of Ottawa Heart Institute @2 Ottawa, Ontario @3 CAN @Z 4 aut. @Z 14 aut.`
A14	`03`			`@1 Imperial College @2 London @3 GBR @Z 11 aut. @Z 12 aut.`
A20				`@1 21-29`
A21				`@1 2005`
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A43	`01`			`@1 INIST @2 5907 @5 354000125001540050`
A44				`@0 0000 @1 © 2005 INIST-CNRS. All rights reserved.`
A45				`@0 25 ref.`
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A60				`@1 P`
A61				`@0 A`
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C01	`01`		`ENG`	@0 Background-We identified a gene (PRKAG2) that encodes the γ-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 α-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 . 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.
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C03	`01`	`X`	`ENG`	`@0 Cardiovascular disease @5 01`
C03	`01`	`X`	`SPA`	`@0 Aparato circulatorio patología @5 01`
C03	`02`	`X`	`FRE`	`@0 Animal @5 02`
C03	`02`	`X`	`ENG`	`@0 Animal @5 02`
C03	`02`	`X`	`SPA`	`@0 Animal @5 02`
C03	`03`	`X`	`FRE`	`@0 Souris @5 03`
C03	`03`	`X`	`ENG`	`@0 Mouse @5 03`
C03	`03`	`X`	`SPA`	`@0 Ratón @5 03`
C03	`04`	`X`	`FRE`	`@0 Tachycardie ventriculaire @2 NM @5 04`
C03	`04`	`X`	`ENG`	`@0 Ventricular tachycardia @2 NM @5 04`
C03	`04`	`X`	`SPA`	`@0 Taquicardia ventricular @2 NM @5 04`
C03	`05`	`X`	`FRE`	`@0 AMP @2 NK @2 FR @5 05`
C03	`05`	`X`	`ENG`	`@0 AMP @2 NK @2 FR @5 05`
C03	`05`	`X`	`SPA`	`@0 AMP @2 NK @2 FR @5 05`
C03	`06`	`X`	`FRE`	`@0 Protein kinase @2 FE @5 06`
C03	`06`	`X`	`ENG`	`@0 Protein kinase @2 FE @5 06`
C03	`06`	`X`	`SPA`	`@0 Protein kinase @2 FE @5 06`
C03	`07`	`X`	`FRE`	`@0 Wolff Parkinson White syndrome @5 07`
C03	`07`	`X`	`ENG`	`@0 Wolff Parkinson White syndrome @5 07`
C03	`07`	`X`	`SPA`	`@0 Wolff Parkinson White síndrome @5 07`
C03	`08`	`X`	`FRE`	`@0 Mutation @5 08`
C03	`08`	`X`	`ENG`	`@0 Mutation @5 08`
C03	`08`	`X`	`SPA`	`@0 Mutación @5 08`
C07	`01`	`X`	`FRE`	`@0 Rodentia @2 NS`
C07	`01`	`X`	`ENG`	`@0 Rodentia @2 NS`
C07	`01`	`X`	`SPA`	`@0 Rodentia @2 NS`
C07	`02`	`X`	`FRE`	`@0 Mammalia @2 NS`
C07	`02`	`X`	`ENG`	`@0 Mammalia @2 NS`
C07	`02`	`X`	`SPA`	`@0 Mammalia @2 NS`
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C07	`03`	`X`	`ENG`	`@0 Vertebrata @2 NS`
C07	`03`	`X`	`SPA`	`@0 Vertebrata @2 NS`
C07	`04`	`X`	`FRE`	`@0 Transferases @2 FE`
C07	`04`	`X`	`ENG`	`@0 Transferases @2 FE`
C07	`04`	`X`	`SPA`	`@0 Transferases @2 FE`
C07	`05`	`X`	`FRE`	`@0 Enzyme @2 FE`
C07	`05`	`X`	`ENG`	`@0 Enzyme @2 FE`
C07	`05`	`X`	`SPA`	`@0 Enzima @2 FE`
C07	`06`	`X`	`FRE`	`@0 Cardiopathie @5 37`
C07	`06`	`X`	`ENG`	`@0 Heart disease @5 37`
C07	`06`	`X`	`SPA`	`@0 Cardiopatía @5 37`
C07	`07`	`X`	`FRE`	`@0 Trouble conduction @5 38`
C07	`07`	`X`	`ENG`	`@0 Conduction disorder @5 38`
C07	`07`	`X`	`SPA`	`@0 Trastorno conducción @5 38`
C07	`08`	`X`	`FRE`	`@0 Trouble excitabilité @5 39`
C07	`08`	`X`	`ENG`	`@0 Excitability disorder @5 39`
C07	`08`	`X`	`SPA`	`@0 Trastorno excitabilidad @5 39`
C07	`09`	`X`	`FRE`	`@0 Trouble rythme cardiaque @5 40`
C07	`09`	`X`	`ENG`	`@0 Arrhythmia @5 40`
C07	`09`	`X`	`SPA`	`@0 Arritmia @5 40`
C07	`10`	`X`	`FRE`	`@0 Préexcitation ventriculaire syndrome @5 41`
C07	`10`	`X`	`ENG`	`@0 Preexcitation ventricular syndrome @5 41`
C07	`10`	`X`	`SPA`	`@0 Preexcitación ventricular síndrome @5 41`
N21				`@1 115`
N44	`01`			`@1 OTO`
N82				`@1 OTO`

Format Inist (serveur)

NO :	PASCAL 05-0173141 INIST
ET :	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
AU :	SIDHU (Jasvinder S.); RAJAWAT (Yadavendra S.); RAMI (Tapan G.); GOLLOB (Michael H.); ZHINONG WANG; RUIYONG YUAN; MARIAN (A. J.); DEMAYO (Francesco J.); WEILBACHER (Donald); TAFFET (George E.); DAVIES (Joanna K.); CARLING (David); KHOURY (Dirar S.); ROBERTS (Robert)
AF :	Baylor College of Medicine/Houston, Tex/Etats-Unis (1 aut., 2 aut., 3 aut., 5 aut., 6 aut., 7 aut., 8 aut., 9 aut., 10 aut., 13 aut.); University of Ottawa Heart Institute/Ottawa, Ontario/Canada (4 aut., 14 aut.); Imperial College/London/Royaume-Uni (11 aut., 12 aut.)
DT :	Publication en série; Niveau analytique
SO :	Circulation : (New York, N.Y.); ISSN 0009-7322; Coden CIRCAZ; Etats-Unis; Da. 2005; Vol. 111; No. 1; Pp. 21-29; Bibl. 25 ref.
LA :	Anglais
EA :	Background-We identified a gene (PRKAG2) that encodes the γ-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 α-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 . 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.
CC :	002B12B03; 002B21E01B; 002B02U02
FD :	Appareil circulatoire pathologie; Animal; Souris; Tachycardie ventriculaire; AMP; Protein kinase; Wolff Parkinson White syndrome; Mutation
FG :	Rodentia; Mammalia; Vertebrata; Transferases; Enzyme; Cardiopathie; Trouble conduction; Trouble excitabilité; Trouble rythme cardiaque; Préexcitation ventriculaire syndrome
ED :	Cardiovascular disease; Animal; Mouse; Ventricular tachycardia; AMP; Protein kinase; Wolff Parkinson White syndrome; Mutation
EG :	Rodentia; Mammalia; Vertebrata; Transferases; Enzyme; Heart disease; Conduction disorder; Excitability disorder; Arrhythmia; Preexcitation ventricular syndrome
SD :	Aparato circulatorio patología; Animal; Ratón; Taquicardia ventricular; AMP; Protein kinase; Wolff Parkinson White síndrome; Mutación
LO :	INIST-5907.354000125001540050
ID :	05-0173141

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Pascal:05-0173141

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<author><name sortKey="Zhinong Wang" sort="Zhinong Wang" uniqKey="Zhinong Wang" last="Zhinong Wang">ZHINONG WANG</name>
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<author><name sortKey="Marian, A J" sort="Marian, A J" uniqKey="Marian A" first="A. J." last="Marian">A. J. Marian</name>
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<author><name sortKey="Demayo, Francesco J" sort="Demayo, Francesco J" uniqKey="Demayo F" first="Francesco J." last="Demayo">Francesco J. Demayo</name>
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<author><name sortKey="Weilbacher, Donald" sort="Weilbacher, Donald" uniqKey="Weilbacher D" first="Donald" last="Weilbacher">Donald Weilbacher</name>
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<author><name sortKey="Taffet, George E" sort="Taffet, George E" uniqKey="Taffet G" first="George E." last="Taffet">George E. Taffet</name>
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<author><name sortKey="Davies, Joanna K" sort="Davies, Joanna K" uniqKey="Davies J" first="Joanna K." last="Davies">Joanna K. Davies</name>
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<author><name sortKey="Carling, David" sort="Carling, David" uniqKey="Carling D" first="David" last="Carling">David Carling</name>
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<author><name sortKey="Khoury, Dirar S" sort="Khoury, Dirar S" uniqKey="Khoury D" first="Dirar S." last="Khoury">Dirar S. Khoury</name>
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<author><name sortKey="Roberts, Robert" sort="Roberts, Robert" uniqKey="Roberts R" first="Robert" last="Roberts">Robert Roberts</name>
<affiliation><inist:fA14 i1="02"><s1>University of Ottawa Heart Institute</s1>
<s2>Ottawa, Ontario</s2>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">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</title>
<author><name sortKey="Sidhu, Jasvinder S" sort="Sidhu, Jasvinder S" uniqKey="Sidhu J" first="Jasvinder S." last="Sidhu">Jasvinder S. Sidhu</name>
<affiliation><inist:fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
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<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
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</author>
<author><name sortKey="Rajawat, Yadavendra S" sort="Rajawat, Yadavendra S" uniqKey="Rajawat Y" first="Yadavendra S." last="Rajawat">Yadavendra S. Rajawat</name>
<affiliation><inist:fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
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</affiliation>
</author>
<author><name sortKey="Rami, Tapan G" sort="Rami, Tapan G" uniqKey="Rami T" first="Tapan G." last="Rami">Tapan G. Rami</name>
<affiliation><inist:fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
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</author>
<author><name sortKey="Gollob, Michael H" sort="Gollob, Michael H" uniqKey="Gollob M" first="Michael H." last="Gollob">Michael H. Gollob</name>
<affiliation><inist:fA14 i1="02"><s1>University of Ottawa Heart Institute</s1>
<s2>Ottawa, Ontario</s2>
<s3>CAN</s3>
<sZ>4 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Zhinong Wang" sort="Zhinong Wang" uniqKey="Zhinong Wang" last="Zhinong Wang">ZHINONG WANG</name>
<affiliation><inist:fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
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<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
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</affiliation>
</author>
<author><name sortKey="Ruiyong Yuan" sort="Ruiyong Yuan" uniqKey="Ruiyong Yuan" last="Ruiyong Yuan">RUIYONG YUAN</name>
<affiliation><inist:fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
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<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
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<author><name sortKey="Marian, A J" sort="Marian, A J" uniqKey="Marian A" first="A. J." last="Marian">A. J. Marian</name>
<affiliation><inist:fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
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<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
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</affiliation>
</author>
<author><name sortKey="Demayo, Francesco J" sort="Demayo, Francesco J" uniqKey="Demayo F" first="Francesco J." last="Demayo">Francesco J. Demayo</name>
<affiliation><inist:fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Weilbacher, Donald" sort="Weilbacher, Donald" uniqKey="Weilbacher D" first="Donald" last="Weilbacher">Donald Weilbacher</name>
<affiliation><inist:fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
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</affiliation>
</author>
<author><name sortKey="Taffet, George E" sort="Taffet, George E" uniqKey="Taffet G" first="George E." last="Taffet">George E. Taffet</name>
<affiliation><inist:fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
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</affiliation>
</author>
<author><name sortKey="Davies, Joanna K" sort="Davies, Joanna K" uniqKey="Davies J" first="Joanna K." last="Davies">Joanna K. Davies</name>
<affiliation><inist:fA14 i1="03"><s1>Imperial College</s1>
<s2>London</s2>
<s3>GBR</s3>
<sZ>11 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Carling, David" sort="Carling, David" uniqKey="Carling D" first="David" last="Carling">David Carling</name>
<affiliation><inist:fA14 i1="03"><s1>Imperial College</s1>
<s2>London</s2>
<s3>GBR</s3>
<sZ>11 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Khoury, Dirar S" sort="Khoury, Dirar S" uniqKey="Khoury D" first="Dirar S." last="Khoury">Dirar S. Khoury</name>
<affiliation><inist:fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>7 aut.</sZ>
<sZ>8 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
<author><name sortKey="Roberts, Robert" sort="Roberts, Robert" uniqKey="Roberts R" first="Robert" last="Roberts">Robert Roberts</name>
<affiliation><inist:fA14 i1="02"><s1>University of Ottawa Heart Institute</s1>
<s2>Ottawa, Ontario</s2>
<s3>CAN</s3>
<sZ>4 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">Circulation : (New York, N.Y.)</title>
<title level="j" type="abbreviated">Circulation : (N. Y. N.Y.)</title>
<idno type="ISSN">0009-7322</idno>
<imprint><date when="2005">2005</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">Circulation : (New York, N.Y.)</title>
<title level="j" type="abbreviated">Circulation : (N. Y. N.Y.)</title>
<idno type="ISSN">0009-7322</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>AMP</term>
<term>Animal</term>
<term>Cardiovascular disease</term>
<term>Mouse</term>
<term>Mutation</term>
<term>Protein kinase</term>
<term>Ventricular tachycardia</term>
<term>Wolff Parkinson White syndrome</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Appareil circulatoire pathologie</term>
<term>Animal</term>
<term>Souris</term>
<term>Tachycardie ventriculaire</term>
<term>AMP</term>
<term>Protein kinase</term>
<term>Wolff Parkinson White syndrome</term>
<term>Mutation</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Background-We identified a gene (PRKAG2) that encodes the γ-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<sub>WT</sub>
) and mutant(TG<sub>R302Q</sub>
) PRKAG2 gene with the cardiac-specific promoter α-myosin heavy chain. ECG recordings and intracardiac electrophysiology studies demonstrated the TG<sub>R302Q</sub>
 mice to have ventricular preexcitation (PR interval 10±2 versus 33±5 ms in TG<sub>WT</sub>
, P<0.05) and a prolonged QRS (20±5 versus 10±1 ms in TG<sub>WT</sub>
, 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<sup>-1</sup>
 . g<sup>-1</sup>
 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<sub>WT</sub>
) 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.</div>
</front>
</TEI>
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<fA08 i1="01" i2="1" l="ENG"><s1>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</s1>
</fA08>
<fA11 i1="01" i2="1"><s1>SIDHU (Jasvinder S.)</s1>
</fA11>
<fA11 i1="02" i2="1"><s1>RAJAWAT (Yadavendra S.)</s1>
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<fA11 i1="03" i2="1"><s1>RAMI (Tapan G.)</s1>
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<fA11 i1="04" i2="1"><s1>GOLLOB (Michael H.)</s1>
</fA11>
<fA11 i1="05" i2="1"><s1>ZHINONG WANG</s1>
</fA11>
<fA11 i1="06" i2="1"><s1>RUIYONG YUAN</s1>
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<fA11 i1="07" i2="1"><s1>MARIAN (A. J.)</s1>
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<fA11 i1="08" i2="1"><s1>DEMAYO (Francesco J.)</s1>
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<fA11 i1="09" i2="1"><s1>WEILBACHER (Donald)</s1>
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<fA11 i1="10" i2="1"><s1>TAFFET (George E.)</s1>
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<fA11 i1="11" i2="1"><s1>DAVIES (Joanna K.)</s1>
</fA11>
<fA11 i1="12" i2="1"><s1>CARLING (David)</s1>
</fA11>
<fA11 i1="13" i2="1"><s1>KHOURY (Dirar S.)</s1>
</fA11>
<fA11 i1="14" i2="1"><s1>ROBERTS (Robert)</s1>
</fA11>
<fA14 i1="01"><s1>Baylor College of Medicine</s1>
<s2>Houston, Tex</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
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</fA14>
<fA14 i1="02"><s1>University of Ottawa Heart Institute</s1>
<s2>Ottawa, Ontario</s2>
<s3>CAN</s3>
<sZ>4 aut.</sZ>
<sZ>14 aut.</sZ>
</fA14>
<fA14 i1="03"><s1>Imperial College</s1>
<s2>London</s2>
<s3>GBR</s3>
<sZ>11 aut.</sZ>
<sZ>12 aut.</sZ>
</fA14>
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<fC01 i1="01" l="ENG"><s0>Background-We identified a gene (PRKAG2) that encodes the γ-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<sub>WT</sub>
) and mutant(TG<sub>R302Q</sub>
) PRKAG2 gene with the cardiac-specific promoter α-myosin heavy chain. ECG recordings and intracardiac electrophysiology studies demonstrated the TG<sub>R302Q</sub>
 mice to have ventricular preexcitation (PR interval 10±2 versus 33±5 ms in TG<sub>WT</sub>
, P<0.05) and a prolonged QRS (20±5 versus 10±1 ms in TG<sub>WT</sub>
, 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<sup>-1</sup>
 . g<sup>-1</sup>
 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<sub>WT</sub>
) 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.</s0>
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<fC03 i1="05" i2="X" l="ENG"><s0>AMP</s0>
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<s2>NS</s2>
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<s5>37</s5>
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<fC07 i1="06" i2="X" l="ENG"><s0>Heart disease</s0>
<s5>37</s5>
</fC07>
<fC07 i1="06" i2="X" l="SPA"><s0>Cardiopatía</s0>
<s5>37</s5>
</fC07>
<fC07 i1="07" i2="X" l="FRE"><s0>Trouble conduction</s0>
<s5>38</s5>
</fC07>
<fC07 i1="07" i2="X" l="ENG"><s0>Conduction disorder</s0>
<s5>38</s5>
</fC07>
<fC07 i1="07" i2="X" l="SPA"><s0>Trastorno conducción</s0>
<s5>38</s5>
</fC07>
<fC07 i1="08" i2="X" l="FRE"><s0>Trouble excitabilité</s0>
<s5>39</s5>
</fC07>
<fC07 i1="08" i2="X" l="ENG"><s0>Excitability disorder</s0>
<s5>39</s5>
</fC07>
<fC07 i1="08" i2="X" l="SPA"><s0>Trastorno excitabilidad</s0>
<s5>39</s5>
</fC07>
<fC07 i1="09" i2="X" l="FRE"><s0>Trouble rythme cardiaque</s0>
<s5>40</s5>
</fC07>
<fC07 i1="09" i2="X" l="ENG"><s0>Arrhythmia</s0>
<s5>40</s5>
</fC07>
<fC07 i1="09" i2="X" l="SPA"><s0>Arritmia</s0>
<s5>40</s5>
</fC07>
<fC07 i1="10" i2="X" l="FRE"><s0>Préexcitation ventriculaire syndrome</s0>
<s5>41</s5>
</fC07>
<fC07 i1="10" i2="X" l="ENG"><s0>Preexcitation ventricular syndrome</s0>
<s5>41</s5>
</fC07>
<fC07 i1="10" i2="X" l="SPA"><s0>Preexcitación ventricular síndrome</s0>
<s5>41</s5>
</fC07>
<fN21><s1>115</s1>
</fN21>
<fN44 i1="01"><s1>OTO</s1>
</fN44>
<fN82><s1>OTO</s1>
</fN82>
</pA>
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<server><NO>PASCAL 05-0173141 INIST</NO>
<ET>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</ET>
<AU>SIDHU (Jasvinder S.); RAJAWAT (Yadavendra S.); RAMI (Tapan G.); GOLLOB (Michael H.); ZHINONG WANG; RUIYONG YUAN; MARIAN (A. J.); DEMAYO (Francesco J.); WEILBACHER (Donald); TAFFET (George E.); DAVIES (Joanna K.); CARLING (David); KHOURY (Dirar S.); ROBERTS (Robert)</AU>
<AF>Baylor College of Medicine/Houston, Tex/Etats-Unis (1 aut., 2 aut., 3 aut., 5 aut., 6 aut., 7 aut., 8 aut., 9 aut., 10 aut., 13 aut.); University of Ottawa Heart Institute/Ottawa, Ontario/Canada (4 aut., 14 aut.); Imperial College/London/Royaume-Uni (11 aut., 12 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Circulation : (New York, N.Y.); ISSN 0009-7322; Coden CIRCAZ; Etats-Unis; Da. 2005; Vol. 111; No. 1; Pp. 21-29; Bibl. 25 ref.</SO>
<LA>Anglais</LA>
<EA>Background-We identified a gene (PRKAG2) that encodes the γ-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<sub>WT</sub>
) and mutant(TG<sub>R302Q</sub>
) PRKAG2 gene with the cardiac-specific promoter α-myosin heavy chain. ECG recordings and intracardiac electrophysiology studies demonstrated the TG<sub>R302Q</sub>
 mice to have ventricular preexcitation (PR interval 10±2 versus 33±5 ms in TG<sub>WT</sub>
, P<0.05) and a prolonged QRS (20±5 versus 10±1 ms in TG<sub>WT</sub>
, 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<sup>-1</sup>
 . g<sup>-1</sup>
 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<sub>WT</sub>
) 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.</EA>
<CC>002B12B03; 002B21E01B; 002B02U02</CC>
<FD>Appareil circulatoire pathologie; Animal; Souris; Tachycardie ventriculaire; AMP; Protein kinase; Wolff Parkinson White syndrome; Mutation</FD>
<FG>Rodentia; Mammalia; Vertebrata; Transferases; Enzyme; Cardiopathie; Trouble conduction; Trouble excitabilité; Trouble rythme cardiaque; Préexcitation ventriculaire syndrome</FG>
<ED>Cardiovascular disease; Animal; Mouse; Ventricular tachycardia; AMP; Protein kinase; Wolff Parkinson White syndrome; Mutation</ED>
<EG>Rodentia; Mammalia; Vertebrata; Transferases; Enzyme; Heart disease; Conduction disorder; Excitability disorder; Arrhythmia; Preexcitation ventricular syndrome</EG>
<SD>Aparato circulatorio patología; Animal; Ratón; Taquicardia ventricular; AMP; Protein kinase; Wolff Parkinson White síndrome; Mutación</SD>
<LO>INIST-5907.354000125001540050</LO>
<ID>05-0173141</ID>
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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

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

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