Novel arterial pathology in mice and humans hemizygous for elastin
Novel arterial pathology in mice and humans hemizygous for elastin
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DOI：
10.1172/jci4487
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发表时间：
1998-11-15
影响因子：
15.9
通讯作者：
Keating, MT
中科院分区：
文献类型：
--
作者：
Li, DY;Faury, G;Keating, MT
阻塞性血管疾病是工业化国家的一个重要健康问题。通过一系列的分子遗传学研究，我们证明了一个弹性蛋白等位基因的功能缺失突变会导致一种遗传性阻塞性动脉疾病，即瓣上主动脉瓣狭窄（SVAS）。为了确定弹性蛋白的作用机制，我们产生了弹性蛋白基因（ELN +/-）的半合子小鼠。尽管ELN +/-小鼠的ELN mRNA和蛋白质减少了50%，但生理压力下的动脉顺应性几乎正常。ELN +/-动脉中弹性膜和平滑肌数量反常增加35%解释了这种差异。对具有ELN半合子的人的检查显示弹性膜和平滑肌增加了2.5倍。因此，ELN半合子在小鼠和人类诱导动脉发育过程中的弹性膜和平滑肌环的数量的代偿性增加。人类对ELN表达的减少非常敏感，发生严重的动脉增厚，并显著增加阻塞性血管疾病的风险。
Obstructive vascular disease is an important health problem in the industrialized world. Through a series of molecular genetic studies, we demonstrated that loss-of-function mutations in one elastin allele cause an inherited obstructive arterial disease, supravalvular aortic stenosis (SVAS). To define the mechanism of elastin's effect, we generated mice hemizygous for the elastin gene (ELN +/-). Although ELN mRNA and protein were reduced by 50% in ELN +/- mice, arterial compliance at physiologic pressures was nearly normal. This discrepancy was explained by a paradoxical increase of 35% in the number of elastic lamellae and smooth muscle in ELN +/- arteries. Examination of humans with ELN hemizygosity revealed a 2.5-fold increase in elastic lamellae and smooth muscle. Thus, ELN hemizygosity in mice and humans induces a compensatory increase in the number of rings of elastic lamellae and smooth muscle during arterial development. Humans are exquisitely sensitive to reduced ELN expression, developing profound arterial thickening and markedly increased risk of obstructive vascular disease.