Endothelin.
Endothelin.
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DOI：
10.1124/pr.115.011833
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发表时间：
2016-04
影响因子：
21.1
通讯作者：
Maguire JJ
中科院分区：
文献类型：
--
作者：
Davenport AP;Hyndman KA;Dhaun N;Southan C;Kohan DE;Pollock JS;Pollock DM;Webb DJ;Maguire JJ
内皮素由三个结构相似的21个氨基酸组成。ET-1和-2以相同的亲和力激活两个G蛋白偶联受体ETA和ETB，而ET-3对ETA亚型的亲和力较低。编码多肽的基因只存在于脊椎动物中。配体-受体信号通路是脊椎动物的一种创新，可能反映了内皮素-1作为人类心血管系统中最有效的血管收缩因子的进化，具有显著的持久作用。高选择性多肽ETA和ETB拮抗剂和ETB激动剂与放射性标记类似物一起，已经准确地描述了在人类和动物模型中的内皮素药理，尽管令人惊讶的是没有发现ETA激动剂。ET拮抗剂(波生坦、氨布里森坦)使肺动脉高压的治疗发生了革命性的变化，下一代拮抗剂表现出更好的疗效(马西坦)。临床试验继续探索新的应用，特别是在肾功能衰竭和减少糖尿病肾病的蛋白尿方面。翻译研究表明，ETB激动剂在化疗和神经保护方面有潜在的好处。然而，证明内皮素转换酶和中性内肽酶的联合抑制剂的临床疗效已被证明是难以捉摸的。通过整体或细胞特异性的敲除、敲入或改变内皮素配体或其靶受体的基因表达，已有28种以上的遗传修饰对小鼠的ET系统进行了修改。这些研究已经确定了内皮素亚型和新的治疗靶点在发育、液体-电解质稳态以及心血管和神经功能中的关键作用。未来，通过小分子表观遗传调节剂、ETB单抗等生物制品以及潜在的信号通路偏向激动剂和拮抗剂，将出现新的药理策略。
The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.
截短的人内皮蛋白受体A由替代剪接产生的A及其在黑色素瘤中的表达产生。
影响因子：
8.8
作者：
Zhang, Y F;Jeffery, S;Burchill, S A;Berry, P A;Kaski, J C;Carter, N D
通讯作者：
Carter, N D