Nkx2-5 pathways and congenital heart disease: Loss of ventricular myocyte lineage progressive cardiomyopathy and complete heart block

被引:339
作者
Pashmforoush, M
Lu, JT
Chen, HY
St Amand, T
Kondo, R
Pradervand, S
Evans, SM
Clark, B
Feramisco, JR
Giles, W
Ho, SY
Benson, DW
Silberbach, M
Shou, WN
Chien, KR [1 ]
机构
[1] Univ Calif San Diego, Inst Mol Med, La Jolla, CA 92093 USA
[2] Univ Calgary, Sch Med, Calgary, AB T2N 4N1, Canada
[3] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England
[4] Univ Cincinnati, Cincinnati, OH 45221 USA
[5] Oregon Hlth & Sci Univ, Portland, OR 97239 USA
[6] Indiana Univ, Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA
关键词
D O I
10.1016/S0092-8674(04)00405-2
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Human mutations in Nkx2-5 lead to progressive cardiomyopathy and conduction defects via unknown mechanisms. To define these pathways, we generated mice with a ventricular-restricted knockout of Nkx2-5, which display no structural defects but have progressive complete heart block, and massive trabecular muscle overgrowth found in some patients with Nkx2-5 mutations. At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells. Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium. Further, BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects. Accordingly, loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease.
引用
收藏
页码:373 / 386
页数:14
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