期刊
CIRCULATION RESEARCH
卷 88, 期 11, 页码 1196-1202出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hh1101.091107
关键词
connexin; development; arrhythmia; electrophysiology; knockout
资金
- NHLBI NIH HHS [2P01-HL3970711, HL36059] Funding Source: Medline
- NICHD NIH HHS [HD36457] Funding Source: Medline
Connexin43 (Cx43) is the principal connexin isoform in the mouse ventricle, where it is thought to provide electrical coupling between cells, Knocking out this gene results in anatomic malformations that nevertheless allow for survival through early neonatal life. We examined electrical wave propagation in the left (LV) and right (RV) ventricles of isolated Cx43 null mutated (Cx43(-/-)), heterozygous (Cx43(+/-)), and wild-type (WT) embryos using high-resolution mapping of voltage-sensitive dye fluorescence. Consistent with the compensating presence of the other connexins, no reduction in propagation velocity was seen in Cx43(-/-) ventricles at postcoital day (dpc) 12.5 compared with WT or Cx43(+/-) ventricles. A gross reduction in conduction velocity was seen in the RV at 15.5 dpc tin cm/second, mean [1 SE confidence interval], WT 9.9 [8.7 to 11.2], Cx43(+/-) 9.9 [9.0 to 10.9], and Cx43(-/-) 2.2 [1.8 to 2.7; P < 0,005]) and in both ventricles at 17.5 dpc tin RV, WT 8.4 [7.6 to 9.3], Cx43(+/-) 8.7 [8.1 to 9.3], and Cx43(-/-) 1.1 [0.1 to 1.3; P < 0,005]; in LV, WT 10.1 [9.4 to 10.7], Cx43(+/-) 8.3 [7.8 to 8.9], and Cx43(-/-) 1.7 [1.3 to 2.1; P < 0.005]) corresponding with the downregulation of Cx40, Cx40 and Cx45 mRNAs were detectable in ventricular homogenates even at 17.5 dpc, probably accounting for the residual conduction function. Neonatal knockout hearts were arrhythmic in vivo as well as ex vivo. This study demonstrates the contribution of Cx43 to the electrical function of the developing mouse heart and the essential role of this gene in maintaining heart rhythm in postnatal life.
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