PCSK6-mediated corin activation is essential for normal blood pressure.
PCSK6-mediated corin activation is essential for normal blood pressure.
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PCSK6介导的corin激活对于正常血压至关重要
DOI：
10.1038/nm.3920
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发表时间：
2015-09
期刊：
影响因子：
82.9
通讯作者：
Wu Q
中科院分区：
文献类型：
--
作者：
Chen S;Cao P;Dong N;Peng J;Zhang C;Wang H;Zhou T;Yang J;Zhang Y;Martelli EE;Naga Prasad SV;Miller RE;Malfait AM;Zhou Y;Wu Q
高血压是最常见的心血管疾病，困扰着>30%的成年人。大多数人高血压的原因仍然未知，这表明尚未发现其他的影响因素。Corin是一种丝氨酸蛋白酶，可激活利钠肽，从而调节血压。它作为一种酶原合成，通过蛋白水解切割激活。在高血压和先兆子痫患者中发现了损害corin激活的CORIN变体和突变，，。然而，迄今为止，激活corin的蛋白酶的身份仍然难以捉摸。在这里，我们表明，前蛋白转化酶枯草杆菌蛋白酶/kexin-6（PCSK 6，也称为PACE 4;参考）切割和激活corin。在培养的细胞中，我们发现corin激活被PCSK家族蛋白酶抑制剂和阻断PCSK 6表达的小干扰RNA抑制。相反，PCSK 6过表达增强corin激活。此外，纯化的PCSK 6能裂解野生型corin，但不能裂解缺少保守激活位点的R801 A变体，敲除PCSK 6的小鼠出现盐敏感性高血压，corin激活和前心房利钠肽加工活性在这些小鼠中检测不到。此外，我们发现高血压和先兆子痫患者的CORIN变体在PCSK 6介导的激活中存在缺陷。我们还发现了一个高血压患者的PCSK 6突变，该突变损害了corin的激活活性。我们的研究结果表明，PCSK 6是长期寻找corin激活剂，是重要的钠稳态和正常的血压。
Hypertension is the most common cardiovascular disease, afflicting >30% of adults. The cause of hypertension in most individuals remains unknown,, suggesting that additional contributing factors have yet to be discovered. Corin is a serine protease that activates the natriuretic peptides, thereby regulating blood pressure. It is synthesized as a zymogen that is activated by proteolytic cleavage.CORINvariants and mutations impairing corin activation have been identified in people with hypertension and pre-eclampsia,,,,. To date, however, the identity of the protease that activates corin remains elusive. Here we show that proprotein convertase subtilisin/kexin-6 (PCSK6, also named PACE4; ref. ) cleaves and activates corin. In cultured cells, we found that corin activation was inhibited by inhibitors of PCSK family proteases and by small interfering RNAs blocking PCSK6 expression. Conversely, PCSK6 overexpression enhanced corin activation. In addition, purified PCSK6 cleaved wild-type corin but not the R801A variant that lacks the conserved activation site.Pcsk6-knockout mice developed salt-sensitive hypertension, and corin activation and pro-atrial natriuretic peptide processing activity were undetectable in these mice. Moreover, we found thatCORINvariants in individuals with hypertension and pre-eclampsia were defective in PCSK6-mediated activation. We also identified aPCSK6mutation that impaired corin activation activity in a hypertensive patient. Our results indicate that PCSK6 is the long-sought corin activator and is important for sodium homeostasis and normal blood pressure.