Cardiac electrophysiological phenotypes in postnatal expression of Nkx2.5 transgenic mice.
Nkx2.5 is a conserved homeodomain (HD) containing a transcription factor essential for early cardiac development. We generated several mutations modeling some patients with congenital heart disease. Transgenic mice (tg) expressing the wildtype Nkx2.5 under beta-myosin heavy chain (MHC) promoter died during the embryonic stage. However, tg mice expressing this mutation under beta-MHC promoter (beta-MHC-TG(I183P)), the wildtype Nkx2.5 (alpha-MHC-TG(wild)), and a putative transcriptionally active mutant (carboxyl-terminus deletion, alpha-MHC-TG(DeltaC)) under alpha-MHC promoter showed postnatal lethal heart failure. Given the profound atrioventricular conduction abnormalities we recently demonstrated in beta-MHC-TG(I183P) mice, the aim of this study was to determine whether alpha-MHC-TG(wild) and alpha-MHC-TG(DeltaC) mutant mice display similar cardiac electrophysiological phenotypes. Surface ECG recordings and in vivo electrophysiology studies were performed in alpha-MHC-TG(wild) mice and controls at 6 weeks of age, and in alpha-MHC-TG(DeltaC) mice and controls at 10 weeks of age. Ambulatory ECG recordings in alpha-MHC-TG(wild) and controls were obtained using an implantable radiofrequency telemetry system. PR prolongation and atrioventricular nodal dysfunction were detected in alpha-MHC-TG(wild) and alpha-MHC-TG(DeltaC) mice. Bradycardia and prolonged PR interval were seen in ambulatory ECG of alpha-MHC-TG(wild) mice compared to controls. Several alpha-MHC-TG(wild) mice died of bradycardia. Fetal and neonatal mutant Nkx2.5 expression causes severe cardiac conduction failure. Postnatal overexpression of nonmutant (wild) Nkx2.5 also causes conduction abnormalities, although the onset is after the neonatal stage. Bradycardia and AV conduction failure may contribute to the lethal heart failure and early mortality.
Wakimoto
Hiroko
H
Department of Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA.
Kasahara
Hideko
H
Maguire
Colin T
CT
Moskowitz
Ivan P G
IP
Izumo
Seigo
S
Berul
Charles I
CI
D000818:Animals; D001283:Atrioventricular Node / Q000502:physiology; D001919:Bradycardia / Q000235:genetics* / Q000662:veterinary; D004562:Electrocardiography; D004594:Electrophysiology; D005314:Embryonic and Fetal Development / Q000235:genetics; D004699:Endocardium / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006329:Heart Conduction System / Q000502:physiology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000502:physiology; D009026:Mortality; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics* / Q000494:pharmacology*
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors