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 : 002A95 ( Main/Exploration ); précédent : 002A94; suivant : 002A96Transgenic 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 [États-Unis] ; Yadavendra S. Rajawat [États-Unis] ; Tapan G. Rami [États-Unis] ; Michael H. Gollob [Canada] ; ZHINONG WANG [États-Unis] ; RUIYONG YUAN [États-Unis] ; A. J. Marian [États-Unis] ; Francesco J. Demayo [États-Unis] ; Donald Weilbacher [États-Unis] ; George E. Taffet [États-Unis] ; Joanna K. Davies [Royaume-Uni] ; David Carling [Royaume-Uni] ; Dirar S. Khoury [États-Unis] ; Robert Roberts [Canada]Source :
- Circulation : (New York, N.Y.) [ 0009-7322 ] ; 2005.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
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 (TGWT) and mutant(TGR302Q) PRKAG2 gene with the cardiac-specific promoter α-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 TGWT, P<0.05) and a prolonged QRS (20±5 versus 10±1 ms in TGWT, 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 TGWT) 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.
Affiliations:
- Canada, Royaume-Uni, États-Unis
- Angleterre, Grand Londres, Texas
- Houston, Londres
- Baylor College of Medicine
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Khoury</name><affiliation wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></affiliation></author><author><name sortKey="Roberts, Robert" sort="Roberts, Robert" uniqKey="Roberts R" first="Robert" last="Roberts">Robert Roberts</name><affiliation wicri:level="1"><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><country>Canada</country><wicri:noRegion>University of Ottawa Heart Institute</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">05-0173141</idno><date when="2005">2005</date><idno type="stanalyst">PASCAL 05-0173141 INIST</idno><idno type="RBID">Pascal:05-0173141</idno><idno type="wicri:Area/PascalFrancis/Corpus">000924</idno><idno type="wicri:Area/PascalFrancis/Curation">000399</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000759</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000759</idno><idno type="wicri:doubleKey">0009-7322:2005:Sidhu J:transgenic:mouse:model</idno><idno type="wicri:Area/Main/Merge">002E27</idno><idno type="wicri:Area/Main/Curation">002A95</idno><idno type="wicri:Area/Main/Exploration">002A95</idno></publicationStmt><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 wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></affiliation></author><author><name sortKey="Rajawat, Yadavendra S" sort="Rajawat, Yadavendra S" uniqKey="Rajawat Y" first="Yadavendra S." last="Rajawat">Yadavendra S. Rajawat</name><affiliation wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></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 wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></affiliation></author><author><name sortKey="Gollob, Michael H" sort="Gollob, Michael H" uniqKey="Gollob M" first="Michael H." last="Gollob">Michael H. Gollob</name><affiliation wicri:level="1"><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><country>Canada</country><wicri:noRegion>University of Ottawa Heart Institute</wicri:noRegion></affiliation></author><author><name sortKey="Zhinong Wang" sort="Zhinong Wang" uniqKey="Zhinong Wang" last="Zhinong Wang">ZHINONG WANG</name><affiliation wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></affiliation></author><author><name sortKey="Ruiyong Yuan" sort="Ruiyong Yuan" uniqKey="Ruiyong Yuan" last="Ruiyong Yuan">RUIYONG YUAN</name><affiliation wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></affiliation></author><author><name sortKey="Marian, A J" sort="Marian, A J" uniqKey="Marian A" first="A. J." last="Marian">A. J. Marian</name><affiliation wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></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 wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></affiliation></author><author><name sortKey="Weilbacher, Donald" sort="Weilbacher, Donald" uniqKey="Weilbacher D" first="Donald" last="Weilbacher">Donald Weilbacher</name><affiliation wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></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 wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></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 wicri:level="3"><inist:fA14 i1="03"><s1>Imperial College</s1><s2>London</s2><s3>GBR</s3><sZ>11 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Carling, David" sort="Carling, David" uniqKey="Carling D" first="David" last="Carling">David Carling</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Imperial College</s1><s2>London</s2><s3>GBR</s3><sZ>11 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></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 wicri:level="4"><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><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><orgName type="university">Baylor College of Medicine</orgName></affiliation></author><author><name sortKey="Roberts, Robert" sort="Roberts, Robert" uniqKey="Roberts R" first="Robert" last="Roberts">Robert Roberts</name><affiliation wicri:level="1"><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><country>Canada</country><wicri:noRegion>University of Ottawa Heart Institute</wicri:noRegion></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><affiliations><list><country><li>Canada</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Grand Londres</li><li>Texas</li></region><settlement><li>Houston</li><li>Londres</li></settlement><orgName><li>Baylor College of Medicine</li></orgName></list><tree><country name="États-Unis"><region name="Texas"><name sortKey="Sidhu, Jasvinder S" sort="Sidhu, Jasvinder S" uniqKey="Sidhu J" first="Jasvinder S." last="Sidhu">Jasvinder S. Sidhu</name></region><name sortKey="Demayo, Francesco J" sort="Demayo, Francesco J" uniqKey="Demayo F" first="Francesco J." last="Demayo">Francesco J. Demayo</name><name sortKey="Khoury, Dirar S" sort="Khoury, Dirar S" uniqKey="Khoury D" first="Dirar S." last="Khoury">Dirar S. Khoury</name><name sortKey="Marian, A J" sort="Marian, A J" uniqKey="Marian A" first="A. J." last="Marian">A. J. Marian</name><name sortKey="Rajawat, Yadavendra S" sort="Rajawat, Yadavendra S" uniqKey="Rajawat Y" first="Yadavendra S." last="Rajawat">Yadavendra S. Rajawat</name><name sortKey="Rami, Tapan G" sort="Rami, Tapan G" uniqKey="Rami T" first="Tapan G." last="Rami">Tapan G. Rami</name><name sortKey="Ruiyong Yuan" sort="Ruiyong Yuan" uniqKey="Ruiyong Yuan" last="Ruiyong Yuan">RUIYONG YUAN</name><name sortKey="Taffet, George E" sort="Taffet, George E" uniqKey="Taffet G" first="George E." last="Taffet">George E. Taffet</name><name sortKey="Weilbacher, Donald" sort="Weilbacher, Donald" uniqKey="Weilbacher D" first="Donald" last="Weilbacher">Donald Weilbacher</name><name sortKey="Zhinong Wang" sort="Zhinong Wang" uniqKey="Zhinong Wang" last="Zhinong Wang">ZHINONG WANG</name></country><country name="Canada"><noRegion><name sortKey="Gollob, Michael H" sort="Gollob, Michael H" uniqKey="Gollob M" first="Michael H." last="Gollob">Michael H. Gollob</name></noRegion><name sortKey="Roberts, Robert" sort="Roberts, Robert" uniqKey="Roberts R" first="Robert" last="Roberts">Robert Roberts</name></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Davies, Joanna K" sort="Davies, Joanna K" uniqKey="Davies J" first="Joanna K." last="Davies">Joanna K. Davies</name></region><name sortKey="Carling, David" sort="Carling, David" uniqKey="Carling D" first="David" last="Carling">David Carling</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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