Targeted disruption of Na+/Ca2+ exchanger gene leads to cardiomyocyte apoptosis and defects in heartbeat

Koji Wakimoto, Kinji Kobayashi, Makoto Kuro-o, Atsushi Yao, Takahiro Iwamoto, Noriyuki Yanaka, Satomi Kita, Atsuyuki Nishida, Sadahiro Azuma, Yutaka Toyoda, Kenji Omori, Hiroshi Imahie, Toru Oka, Sumiyo Kudoh, Osami Kohmoto, Yoshio Yazaki, Munekazu Shigekawa, Yuji Imai, Yo Ichi Nabeshima, Issei Komuro

Research output: Contribution to journalArticlepeer-review

175 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)36991-36998
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number47
DOIs
StatePublished - Nov 24 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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