Physiologic and pathophysiologic role of C-type natriuretic peptide

1. CNP敲除和CNP转基因小鼠的产生和分析：为了研究CNP在体内的生理学意义，我们产生了具有CNP靶向破坏的小鼠（CNP-<-1->小鼠）。CNP-4<-1->小鼠由于软骨内骨化受损而显示出严重的侏儒症。它们在围产期都能存活，但不到一半能在产后发育中存活。骨骼表型在组织学上与软骨发育不全患者相似，软骨发育不全是人类侏儒症最常见的遗传形式。CNP在生长板软骨细胞中的靶向表达可以挽救CNP+小鼠的骨骼缺陷<-1->并允许其延长存活。这项研究表明CNP在体内局部作为软骨内骨化的正性调节剂，并提示其在某些形式的骨骼发育不良中的病理生理学和治疗意义。2. BNP转基因小鼠和GC-A敲除小鼠之间的遗传交叉：BNP，一种主要由心室产生的激素， ...更多信息 被认为通过其同源受体鸟苷酸环化酶A（GC-A）参与多种稳态过程。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^<-1->小鼠），并检查了它们的心血管和骨骼表型。相对<-1->于野生型同窝出生的小鼠，GC-A+小鼠是高血压伴心脏肥大的，这并不因BNP在BNP-Tg/GC-A+小鼠中的过表达而减轻<-1->。然而，BNP-Tg/GC-A+<-1->小鼠继续表现出与BNP-Tg小鼠不同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+<-1->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。少

1.Generation and Analysis of CNP-knockout and CNP-transgenic mice :To investigate the physiological significance of CNP in vivo, we generated mice with targeted disruption of CNP (CNP^<-1-> mice). The CNP^<-1-> mice show severe dwarfism as a result of impaired endochondral ossification. They are all viable perinatally, but less than half can survive during postnatal development. The skeletal phenotypes are histologically similar to those seen in patients with achondroplasia, the most common genetic form of human dwarfism. Targeted expression of CNP in the growth plate chondrocytes can rescue the skeletal defect of CNP^<-1-> mice and allow their prolonged survival. This study demonstrates that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggests its pathophysiological and therapeutic implication in some forms of skeletal dysplasia.2.Genetic cross between BNP-transgenic and GC-A knockout mice :BNP, a hormone produced primarily by the cardiac ventricl … More e, is thought to be involved in a variety of homeostatic processes through its cognate receptor, guanylyl cyclase A (GC-A). To address whether BNP exerts its biological effects solely through GC-A, we produced BNP-transgenic mice lacking GC-A (BNP-Tg/GC-A^<-1-> mice) and examined their cardiovascular and skeletal phenotypes. The GC-A^<-1-> mice are hypertensive with cardiac hypertrophy relative to wild-type littermates, which is not alleviated by overexpression of BNP in BNP-Tg/GC-A^<-1-> mice. The BNP-Tg/GC-A^<-1-> 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^<-1-> 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. Less