title: Targeted disruption of Na+/Ca2+ exchanger gene leads to cardiomyocyte apoptosis and defects in heartbeat.
abstract: Ca(2+), which enters cardiac myocytes through voltage-dependent Ca(2+) channels during excitation, is extruded from myocytes primarily by the Na(+)/Ca(2+) exchanger (NCX1) during relaxation. The increase in intracellular Ca(2+) concentration in myocytes by digitalis treatment and after ischemia/reperfusion is also thought to result from the reverse mode of the Na(+)/Ca(2+) exchange mechanism. However, the precise roles of the NCX1 are still unclear because of the lack of its specific inhibitors. We generated Ncx1-deficient mice by gene targeting to determine the in vivo function of the exchanger. Homozygous Ncx1-deficient mice died between embryonic days 9 and 10. Their hearts did not beat, and cardiac myocytes showed apoptosis. No forward mode or reverse mode of the Na(+)/Ca(2+) exchange activity was detected in null mutant hearts. The Na(+)-dependent Ca(2+) exchange activity as well as protein content of NCX1 were decreased by approximately 50% in the heart, kidney, aorta, and smooth muscle cells of the heterozygous mice, and tension development of the aortic ring in Na(+)-free solution was markedly impaired in heterozygous mice. These findings suggest that NCX1 is required for heartbeats and survival of cardiac myocytes in embryos and plays critical roles in Na(+)-dependent Ca(2+) handling in the heart and aorta.
authors.affiliation: Advanced Medical Research Department and Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd., 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Wakimoto
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Kuro-O
authors.forename: A
authors.initials: A
authors.lastname: Yao
authors.forename: T
authors.initials: T
authors.lastname: Iwamoto
authors.forename: N
authors.initials: N
authors.lastname: Yanaka
authors.forename: S
authors.initials: S
authors.lastname: Kita
authors.forename: A
authors.initials: A
authors.lastname: Nishida
authors.forename: S
authors.initials: S
authors.lastname: Azuma
authors.forename: Y
authors.initials: Y
authors.lastname: Toyoda
authors.forename: K
authors.initials: K
authors.lastname: Omori
authors.forename: H
authors.initials: H
authors.lastname: Imahie
authors.forename: T
authors.initials: T
authors.lastname: Oka
authors.forename: S
authors.initials: S
authors.lastname: Kudoh
authors.forename: O
authors.initials: O
authors.lastname: Kohmoto
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: M
authors.initials: M
authors.lastname: Shigekawa
authors.forename: Y
authors.initials: Y
authors.lastname: Imai
authors.forename: Y
authors.initials: Y
authors.lastname: Nabeshima
authors.forename: I
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D017209:Apoptosis; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D005091:Exons; D006321:Heart / Q000502:physiology*; D017403:In Situ Hybridization; D051379:Mice; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000166:cytology*; D010920:Placenta / Q000737:chemistry; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics* / Q000502:physiology; D015017:Yolk Sac / Q000737:chemistry
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1