Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system.
Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system.
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DOI：
10.1016/j.tips.2015.06.002
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发表时间：
2015-09
影响因子：
13.8
通讯作者：
Davenport AP
中科院分区：
文献类型：
--
作者：
Yang P;Maguire JJ;Davenport AP
一种偏向性爱帕琳受体激动剂显示了在临床中实用的概念验证。Elabela/Toddler是一种新的心血管系统apelin受体配体。增强apelin信号传导在肺动脉高压中是有益的。Apelin及其G蛋白偶联受体（GPCR）已成为心血管系统中的关键信号通路。该肽是一种有效的正性肌力剂和血管扩张剂。值得注意的是，与爱帕琳几乎没有序列相似性的肽Elabela/Toddler已被提出作为第二种内源性爱帕琳受体配体，并且由来自先前分类为“非编码”的基因组区域的基因编码。Apelin在肺动脉高压和心力衰竭中下调。为了替代缺失的内源性肽，已经设计了“偏向性”爱帕琳激动剂，其优先激活G蛋白途径，导致β-抑制蛋白募集和受体内化减少，具有减弱有害的β-抑制蛋白信号传导的额外益处。概念验证研究支持爱帕琳受体偏向激动剂的临床潜力。
A biased apelin receptor agonist shows proof-of-concept for utility in the clinic. Elabela/Toddler is a new apelin receptor ligand in the human cardiovascular system. Enhancing apelin signalling is beneficial in pulmonary arterial hypertension. Apelin and its G protein-coupled receptor (GPCR) have emerged as a key signalling pathway in the cardiovascular system. The peptide is a potent inotropic agent and vasodilator. Remarkably, a peptide, Elabela/Toddler, that has little sequence similarity to apelin, has been proposed as a second endogenous apelin receptor ligand and is encoded by a gene from a region of the genome previously classified as ‘non-coding’. Apelin is downregulated in pulmonary arterial hypertension and heart failure. To replace the missing endogenous peptide, ‘biased’ apelin agonists have been designed that preferentially activate G protein pathways, resulting in reduced β-arrestin recruitment and receptor internalisation, with the additional benefit of attenuating detrimental β-arrestin signalling. Proof-of-concept studies support the clinical potential for apelin receptor biased agonists.