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首页> 外文期刊>Molecular and Cellular Biology >Loss of Endothelial Furin Leads to Cardiac Malformation and Early Postnatal Death
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Loss of Endothelial Furin Leads to Cardiac Malformation and Early Postnatal Death

机译：内皮弗林蛋白酶的丢失导致心脏畸形和出生后早期死亡

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In mammals, seven proprotein convertases (PCs) cleave secretory proteins after basic residues, and four of them are called furin-like PCs: furin, PC5, PACE4, and PC7. In vitro, they share many substrates. However, furin is essential during development since deficient embryos die at embryonic day 11 and exhibit multiple developmental defects, particularly defects related to the function of endothelial cells. To define the role of furin in endothelial cells, an endothelial cell-specific knockout (ecKO) of the Furin gene was generated. Newborns die shortly after birth, indicating that furin is essential in these cells. Magnetic resonance imaging revealed that ecKO embryos exhibit ventricular septal defects (VSD) and/or valve malformations. In addition, primary cultures of wild-type and ecKO lung endothelial cells revealed that ecKO cells are unable to grow. Growth was efficiently rescued by extracellular soluble furin. Analysis of the processing of precursors of endothelin-1 (ET-1), adrenomedullin (Adm), transforming growth factor β1 (TGF-β1), and bone morphogenetic protein 4 (BMP4) confirmed that ET-1, Adm, and TGF-β1 are in vivo substrates of endothelial furin. Mature ET-1 and BMP4 forms were reduced by ～90% in ecKO purified endothelial cells from lungs.
机译：在哺乳动物中，有七个原蛋白转化酶（PC）在碱性残基后裂解分泌蛋白，其中四个被称为弗林蛋白酶样PC：弗林蛋白酶，PC5，PACE4和PC7。 体外，它们共享许多底物。然而，弗林蛋白酶在发育过程中是必不可少的，因为缺乏的胚胎会在胚胎第11天死亡，并表现出多种发育缺陷，特别是与内皮细胞功能有关的缺陷。为了确定弗林蛋白酶在内皮细胞中的作用，产生了弗林蛋白酶基因的内皮细胞特异性敲除（ecKO）。新生儿在出生后不久就死亡，表明弗林蛋白酶在这些细胞中是必不可少的。磁共振成像显示ecKO胚胎表现出室间隔缺损（VSD）和/或瓣膜畸形。此外，野生型和ecKO肺内皮细胞的原代培养表明ecKO细胞无法生长。细胞外可溶性弗林蛋白酶可有效地挽救生长。对内皮素1（ET-1），肾上腺髓质素（Adm），转化生长因子β1（TGF-β1）和骨形态发生蛋白4（BMP4）的前体进行加工分析，证实了ET-1，Adm和TGF- β1是内皮弗林蛋白酶的体内底物。 ecKO纯化的肺内皮细胞中成熟的ET-1和BMP4形式减少了约90％。

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