Endothelin-1: Biosynthesis, Signaling and Vasoreactivity
Endothelin-1: Biosynthesis, Signaling and Vasoreactivity
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DOI：
10.1016/bs.apha.2016.05.002
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发表时间：
2016-01-01
期刊：
影响因子：
--
通讯作者：
D'Orleans-Juste, P.
中科院分区：
文献类型：
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作者：
Houde, M.;Desbiens, L.;D'Orleans-Juste, P.
内皮素-1（ET-1）是一种非常有效的血管收缩肽，最初从内皮细胞分离。它的合成主要在基因转录水平上调节，包括通过弗林蛋白酶型前蛋白转化酶将前体加工成无活性的中间体大ET-1。后一种肽然后可以被内皮素转化酶（ECE）直接切割成ET-1，或者通过两步过程达到活性代谢物，所述两步过程涉及糜蛋白酶将大ET-1水解成ET-1（1-31），其本身需要被脑啡肽酶（NEP）转化成ET-1以发挥生理活性。ET-1通过两种G蛋白偶联受体内皮素受体A（ETA）和内皮素受体B（ET B）进行信号传导。这两种受体均诱导细胞内Ca 2+增加，主要通过电压非依赖性机制（受体操纵通道和钙库操纵通道）从细胞外空间增加。ET-1还通过表皮生长因子受体反式激活、氧化应激诱导、rho激酶和腺苷酸环化酶/环磷酸腺苷途径的激活（ETA）或抑制（ETB）来诱导信号传导。动脉血管收缩主要由ETA受体介导。ET-1通过位于内皮的ETB，在平滑肌上的相同受体类型激活后舒张动脉或收缩血管，在那里它可以与ETA相互作用。此外，ETB依赖性血管收缩似乎在静脉血管系统中更为突出。更好地了解ET-1是如何合成的，以及ETA和ETB受体如何相互作用，可以帮助设计更好的药物治疗心血管疾病，其中靶向ET-1系统的指示。
Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide originally isolated from endothelial cells. Its synthesis, mainly regulated at the gene transcription level, involves processing of a precursor by a furin-type proprotein convertase to an inactive intermediate, big ET-1. The latter peptide can then be cleaved directly by an endothelin-converting enzyme (ECE) into ET-1 or reach the active metabolite through a two-step process involving chymase hydrolyzing big ET-1 to ET-1 (1-31), itself needing conversion to ET-1 by neprilysin (NEP) to exert physiological activity. ET-1 signals through two G protein-coupled receptors, endothelin receptor A (ETA) and endothelin receptor B (ETB). Both receptors induce an increase in intracellular Ca2+, mainly from the extracellular space through voltage-independent mechanisms, the receptor-operated channels and store-operated channels. ET-1 also induces signaling through epidermal growth factor receptor transactivation, oxidative stress induction, rho-kinase, and the activation (ETA) or inhibition (ETB) of the adenylate cyclase/cyclic adenosine monophosphate pathway. Arterial vasoconstriction is mediated mainly by the ETA receptor. ET-1, via endothelium-located ETB, relaxes arteries or constricts vessels following activation of the same receptor type on the smooth muscle, where it can interact with ETA. In addition, ETB-dependent vasoconstriction seems more prominent in the venous vasculature. A better understanding of how ET-1 is synthesized and how ETA and ETB receptors interact could help design better pharmacological agents in the treatment of cardiovascular diseases where targeting the ET-1 system is indicated.