Targeted Disruption of Na+/Ca2+ Exchanger Gene Leads to Cardiomyocyte Apoptosis and Defects in Heartbeat

• Published in: The Journal of biological chemistry Vol. 275; no. 47; pp. 36991 - 36998
• Main Authors: Wakimoto, Koji, Kobayashi, Kinji, Kuro-o, Makoto, Yao, Atsushi, Iwamoto, Takahiro, Yanaka, Noriyuki, Kita, Satomi, Nishida, Atsuyuki, Azuma, Sadahiro, Toyoda, Yutaka, Omori, Kenji, Imahie, Hiroshi, Oka, Toru, Kudoh, Sumiyo, Kohmoto, Osami, Yazaki, Yoshio, Shigekawa, Munekazu, Imai, Yuji, Nabeshima, Yo-ichi, Komuro, Issei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.11.2000; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Apoptosis; Arrhythmias, Cardiac - genetics; Exons; Heart - physiology; In Situ Hybridization; Mice; Mice, Mutant Strains; Myocardium - cytology; Placenta - chemistry; Platelet Endothelial Cell Adhesion Molecule-1 - chemistry; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Sodium-Calcium Exchanger - genetics; Sodium-Calcium Exchanger - physiology; Yolk Sac - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M004035200

Ca2+, which enters cardiac myocytes through voltage-dependent Ca2+channels during excitation, is extruded from myocytes primarily by the Na+/Ca2+ exchanger (NCX1) during relaxation. The increase in intracellular Ca2+ concentration in myocytes by digitalis treatment and after ischemia/reperfusion is also thought to result from the reverse mode of the Na+/Ca2+ 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+/Ca2+ exchange activity was detected in null mutant hearts. The Na+-dependent Ca2+ exchange activity as well as protein content of NCX1 were decreased by ∼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 Ca2+ handling in the heart and aorta.