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

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, Tôru; Kudoh, Sumiyo; Kohmoto, Osami; Yazaki, Yoshio; Shigekawa, Munekazu; Imai, Yuji; Nabeshima, Yo Ichi; Komuro, Issei

doi:10.1074/jbc.m004035200

Cited by 192 publications

(153 citation statements)

References 30 publications

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“…These observations suggest that NCX1 is critical to early cardiac development. Other groups also reported similar cardiac defect induced lethality in the NCX1 KO mice (Wakimoto et al, 2000;Koushik et al, 2001). Recent report showed that transgenic re-expression of a NCX1 isoform was insufficient to rescue a lethal phenotype of NCX1 KO mice (Conway et al, 2002).…”

Section: Introductionmentioning

confidence: 74%

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Partial rescue of the Na+-Ca2+ exchanger (NCX1) knock-out mouse by transgenic expression of NCX1

Cho

Lee²,

Shin³

et al. 2003

Exp Mol Med

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The null mutation of cardiac Na + -Ca 2+ exchanger (NCX1) gene in mice caused death of embryo in utero at embryonic day (ED) 9.0-9.5 and this embryonic lethality appears resulted from abnormal heart development. In the present study, we investigated whether transgenic re-expression of NCX1 in mutant cardiac myocytes could rescue these lethal defects. Transgenic mice expressing the canine NCX1 in a cardiac specific manner were bred into the NCX1 knock-out background but did not prevent the fetal lethality associated with the NCX1 null allele. However, the NCX1 knock-out embryos with an NCX1 transgene survived with heart beatings until ED 10.5 which was one day longer than the survival of the NCX1 knock-out embryos (ED 9.5). At ED 10.5, however, the partially rescued NCX1 embryos might have succumbed to the lack of an organized vasculature in the yolk sacs. The placental labyrinth layer was reduced in size and largely avascular. The transgenic re-expression of NCX1 rescued heart beatings and survived longer, but was still insufficient for the mice to be completely rescued. Importantly, NCX1 was observed to express in the yolk sac and the placenta of wild type mice. The results suggest that defects in extra-embryonic compartments are causal to the lethality, and that NCX1 may play an important role in establishing vascularization in extra-em bryonic tissues.

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Section: Introductionmentioning

confidence: 74%

“…The null mutation of the NCX1 gene caused lethality in mice embryos (Cho et al, 2000;Wakimoto et al, 2000;Koushik et al, 2001;Rheuter et al, 2002). Within embryonic day (ED) 9.0-9.5, the heart of the knock-out (KO) mice showed an irregular contraction and a pericardial effusion (Cho et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Partial rescue of the Na+-Ca2+ exchanger (NCX1) knock-out mouse by transgenic expression of NCX1

Cho

Lee²,

Shin³

et al. 2003

Exp Mol Med

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“…During the revision of our manuscript, this result was recently substantiated from two independent studies on NCX-1-deficient mice in which hearts form, but do not beat (Wakimoto et al, 2000;Koushik et al, 2001). In the stage 11-12 chick embryo within 8 hr of KB-R7943 exposure, heart rate is significantly reduced and, by 22 hr, is totally arrested while control hearts are still beating.…”

Section: Kb-r7943 Inhibitionmentioning

confidence: 80%

Sodium‐calcium exchanger (NCX‐1) and calcium modulation: NCX protein expression patterns and regulation of early heart development

Linask

Han

Artman

et al. 2001

Developmental Dynamics

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Ouabain-induced inhibition of early heart development indicated that Na/K-ATPase plays an important role in maintaining normal ionic balances during differentiation of cardiomyocytes (Linask and Gui [1995] In order to identify a connection between heart development and NCX-mediated Ca ؉؉ regulation, we determined the embryonic spatiotemporal protein expression pattern of NCX-1 during early developmental stages. In both chick and mouse embryos, NCX-1 (the cardiac NCX isoform) is asymmetrically expressed during gastrulation; in the right side of the Hensen's node in the chick, in the right lateral mesoderm in the mouse. At slightly later stages, NCX-1 is expressed in the heart fields at comparable stages of heart development, in the chick at stage 7 and in the mouse at embryonic day (ED) 7.5. By ED 8 in the mouse, the exchanger protein displays a rostrocaudal difference in cardiac expression and an outer curvature-inner curvature ventricular difference. By ED 9.5, cardiac expression has increased from that seen at ED8 and NCX-1 is distributed throughout the myocardium consistent with the possibility that it is important in regulating initial cardiac contractile function. Only a low level of expression is detected in inflow and outflow regions. To substantiate a role for the involvement of calcium-mediated signaling, using pharmacologic approaches, ionomycin (a Ca ؉؉ ionophore) was shown to perturb cardiac cell differentiation in a manner similar to ouabain as assayed by cNkx2.5 and sarcomeric myosin heavy chain expression. In addition, we show that an inhibitor of NCX, KB-R7943, can similarly and adversely affect early cardiac development at stage 4/5 and arrests cardiac cell contractility in 12-somite embryos. Thus, based upon NCX-1 protein expression patterns in the embryo, experimental Ca ؉؉ modulation, and inhibition of NCX activity by KB-R7943, these results suggest an early and central role for calcium-mediated signaling in cardiac cell differentiation and NCX's regulation of the initial heartbeats in the embryo.

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“…These mice were originally described as having embryonic lethal vascular patterning defects, but a subsequent study demonstrated prolonged embryonic viability with cardiomyocyte-specific restoration of NFAT function (Graef et al, 2001a;Bushdid et al, 2003). The dependence of vascular development on cardiac function also has been demonstrated in mice deficient in Ncadherin or the sodium/calcium exchanger Ncx1 (Wakimoto et al, 2000;Luo et al, 2001). The requirement for cardiac function for vascular plexus remodeling was observed as early as 1918, when W.B.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin signaling in avian cardiovascular development

Liberatore

Yutzey

2003

Developmental Dynamics

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Experiments were initiated in avian embryos to determine the embryonic expression of calcineurin protein phosphatase isoforms as well as to identify developmental processes affected by inhibition of calcineurin signal transduction. Chicken calcineurin A alpha (CnA␣) and calcineurin A beta (CnA␤) are differentially expressed in the developing cardiovascular system, including primitive heart tube and valve primordia. Inhibition of calcineurin signaling by cyclosporin A (CsA) treatment in ovo resulted in distinct cardiovascular malformations, depending on the timing and localization of treatment. Initial formation of the heart tube was apparently normal in embryos treated with CsA from embryonic day (E)1 to E2, but hallmarks of heart failure were apparent with treatment from E2 to E3. Vascular defects were apparent in whole embryos treated on either day, but local administration of CsA directly to the forming vessels on E2 did not inhibit blood vessel formation. This observation supports an indirect effect of calcineurin inhibition on angiogenic remodeling as a result of compromised heart development. Together these studies are consistent with multiple roles for calcineurin signaling in the developing cardiovascular system.

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

Cited by 192 publications

References 30 publications

Partial rescue of the Na+-Ca2+ exchanger (NCX1) knock-out mouse by transgenic expression of NCX1

Partial rescue of the Na+-Ca2+ exchanger (NCX1) knock-out mouse by transgenic expression of NCX1

Sodium‐calcium exchanger (NCX‐1) and calcium modulation: NCX protein expression patterns and regulation of early heart development

Calcineurin signaling in avian cardiovascular development

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