TY - JOUR
T1 - Targeted disruption of Na+/Ca2+ exchanger gene leads to cardiomyocyte apoptosis and defects in heartbeat
AU - Wakimoto, Koji
AU - Kobayashi, Kinji
AU - Kuro-o, Makoto
AU - Yao, Atsushi
AU - Iwamoto, Takahiro
AU - Yanaka, Noriyuki
AU - Kita, Satomi
AU - Nishida, Atsuyuki
AU - Azuma, Sadahiro
AU - Toyoda, Yutaka
AU - Omori, Kenji
AU - Imahie, Hiroshi
AU - Oka, Toru
AU - Kudoh, Sumiyo
AU - Kohmoto, Osami
AU - Yazaki, Yoshio
AU - Shigekawa, Munekazu
AU - Imai, Yuji
AU - Nabeshima, Yo Ichi
AU - Komuro, Issei
PY - 2000/11/24
Y1 - 2000/11/24
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M004035200
DO - 10.1074/jbc.M004035200
M3 - Article
C2 - 10967099
AN - SCOPUS:0034711286
SN - 0021-9258
VL - 275
SP - 36991
EP - 36998
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 47
ER -