Genetic models reveal that brain natriuretic peptide can signal through different tissue-specific receptor-mediated pathways
Genetic models reveal that brain natriuretic peptide can signal through different tissue-specific receptor-mediated pathways
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DOI：
10.1210/en.141.10.3807
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发表时间：
2000-10-01
期刊：
影响因子：
4.8
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Chusho, H;Ogawa, Y;Nakao, K
脑利钠肽（BNP）是一种主要由心室产生的激素，被认为通过其同源受体鸟苷酸环化酶A（GC-A）参与各种稳态过程。我们先前创建了在肝脏特异性人血清淀粉样蛋白P组分启动子控制下过表达BNP的转基因小鼠（BNP转基因小鼠），并证明它们表现出血压和心脏重量降低，伴有血浆cGMP浓度升高，并通过激活软骨内骨化显着骨骼过度生长。为了解决BNP是否仅通过GC-A发挥其生物学作用，我们产生了缺乏GC-A的BNP转基因小鼠（BNP-Tg/GC-A（-/-）小鼠），并检查了它们的心血管和骨骼表型。GC-A（-/-）小鼠相对于野生型同窝出生小鼠具有高血压伴心脏肥大，这并不因BNP在BNP-Tg/GC-A（-/-）小鼠中的过表达而减轻;然而，BNP-Tg/GC-A（-/-）小鼠继续表现出与BNP-Tg小鼠相似的椎骨和长骨的显著纵向生长。这项研究提供了遗传学证据，表明BNP通过GC-A降低血压和心脏重量，而在缺乏这种受体的情况下，它会显着改变软骨内骨化。因此，BNP-Tg/GC-A（-/-）小鼠提供了第一个实验模型，证明这种利钠肽可以通过GC-A以外的受体以组织特异性方式发出信号。
Brain natriuretic peptide (BNP), a hormone produced primarily by the cardiac ventricle, is thought to be involved in a variety of homeostatic processes through its cognate receptor, guanylyl cyclase A (GC-A). We previously created transgenic mice overexpressing BNP under the control of the liver-specific human serum amyloid P component promoter (BNP-transgenic mice) and demonstrated that they exhibit reduced blood pressure and cardiac weight accompanied by an elevation of plasma cGMP concentrations and marked skeletal overgrowth through the activation of endochondral ossification. To address whether BNP exerts its biological effects solely through GC-A, we produced BNP-transgenic mice lacking GC-A (BNP-Tg/GC-A(-/-) mice) and examined their cardiovascular and skeletal phenotypes. The GC-A(-/-) mice are hypertensive with cardiac hypertrophy relative to wild-type littermates, which is not alleviated by overexpression of BNP in BNP-Tg/GC-A(-/-) mice; The BNP-Tg/GC-A(-/-) mice, however, continue to exhibit marked longitudinal growth of vertebrae and long bones comparably to BNP-Tg mice. This study provides genetic evidence that BNP reduces blood pressure and cardiac weight through GC-A, whereas it dramatically alters endochondral ossification in the absence of this receptor. Therefore, the BNP-Tg/GC-A(-/-) mice provide the first experimental model demonstrating that this natriuretic peptide can signal in a tissue-specific manner through a receptor other than GC-A.