Hypertension in mice lacking the proatrial natriuretic peptide convertase corin
Hypertension in mice lacking the proatrial natriuretic peptide convertase corin
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DOI：
10.1073/pnas.0407234102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Wu, QY
中科院分区：
文献类型：
--
作者：
Chan, JCY;Knudson, O;Wu, QY
心房利钠肽（ANP）是一种调节血压的心脏激素。在心肌细胞中，该激素被合成为前体心房利钠肽（pro-ANP），其被蛋白水解转化为活性ANP。Corin是一种心脏跨膜丝氨酸蛋白酶，已被证明在体外加工前心钠素，但其生理重要性尚未确定。在这里，我们表明，corin缺陷（Cor（-/-））小鼠在胚胎发育过程中正常发育，并存活到出生后的生活。Cor（-/-）小鼠与WT同窝小鼠相比具有升高的pro-ANP水平，但没有可检测的ANP水平。输注活性重组可溶性corin可短暂恢复ANP前体转化，从而释放循环中具有生物活性的ANP。采用无线电遥测技术测量血压，我们发现Cor（-/-）小鼠与WT小鼠相比具有自发性高血压，并且在饮食盐负荷后增强。怀孕的Cor（-/-）小鼠表现出妊娠晚期蛋白尿和妊娠期间高血压的增加。此外，Cor（-/-）小鼠表现出心脏肥大，导致生命后期心脏功能轻度下降。因此，我们的数据建立corin作为生理前心钠素转化酶，并表明corin缺乏可能有助于高血压性心脏病。
Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood pressure. in cardiomyocytes, the hormone is synthesized as a precursor, proatrial natriuretic peptide (pro-ANP), which is proteolytically converted to active ANP. Corin is a cardiac transmembrane serine protease that has been shown to process pro-ANP in vitro, but its physiological importance had not been established. Here, we show that corin-deficient (Cor(-/-)) mice develop normally during embryogenesis and survive to postnatal life. Cor(-/-) mice have elevated levels of pro-ANP but no detectable levels of ANP as compared with WT littermates. Infusion of an active recombinant soluble corin transiently restores pro-ANP conversion, resulting in the release of circulating biologically active ANP. Using radiotelemetry to assess blood pressure, we find that Cor(-/-) mice have spontaneous hypertension as compared with WT mice, and it is enhanced after dietary salt loading. Pregnant Cor(-/-) mice demonstrate late-gestation proteinuria and enhanced high blood pressure during pregnancy. In addition, Cor(-/-) mice exhibit cardiac hypertrophy resulting in a mild decline in cardiac function later in life. Thus, our data establish corin as the physiological pro-ANP convertase and indicate that corin deficiency may contribute to hypertensive heart disease.