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

J Biol Chem. 2000 Nov 24;275(47):36991-8. doi: 10.1074/jbc.M004035200.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Platelet Endothelial Cell Adhesion Molecule-1
  • Sodium-Calcium Exchanger
  • sodium-calcium exchanger 1