Cardioprotective Angiotensin-(1-7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor
Cardioprotective Angiotensin-(1-7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor
复制标题
DOI：
10.1161/hypertensionaha.116.08118
复制
发表时间：
2016-12-01
期刊：
影响因子：
8.3
通讯作者：
Gales, Celine
中科院分区：
文献类型：
--
作者：
Galandrin, Segolene;Denis, Colette;Gales, Celine
肾素-血管紧张素-醛固酮系统通过血管紧张素II(Ang II)/Ang II 1型受体(AT1-R)轴的过度活动构成高血压的标志。最近的发现表明，只有AT1-R信号通路的一部分是有害的，它们被有偏见的配体选择性抑制会促进治疗效果。到目前为止，只有人工合成的有偏见的配体被描述，并且天然的肾素-血管紧张素-醛固酮系统多肽是否在AT1-R表现出功能选择性仍然是未知的。在这项研究中，我们系统地检测了Ang II、Ang III、Ang IV和Ang-(1-7)在表达AT1-R的HEK293T细胞中激活心脏有害G蛋白和心脏保护抑制蛋白2的有效性和效力。Ang III和Ang IV完全激活与典型的AT1-R激动剂Ang II相似的G蛋白，尽管Ang IV的效力较弱。有趣的是，与AT1-R结合的Ang-(1-7)不能促进G蛋白的激活，而是作为Ang II/GI和Ang II/GQ通路的竞争性拮抗剂。相反，所有肾素-血管紧张素-醛固酮系统多肽都在AT1-R/-arrestin2轴上作为激动剂，但根据它们的效力和AT1-R/-arrestin2细胞内路线的不同，相对于Ang II表现出偏向的活性。重要的是，我们揭示了Ang-(1-7)是一种已知的Mas受体特异性配体，是一种AT1-R偏向激动剂，选择性地促进Arrestin的激活，同时阻断有害的Ang II/AT1-R/GQ轴。Ang-(1-7)at AT1-R类似于合成的AT1-R偏向激动剂的这种原始药理学特征，可能在一定程度上有助于其对心血管的好处。因此，在体内，Ang-(1-7)抵消了苯肾上腺素诱导的主动脉收缩，这种收缩在AT1-R基因敲除小鼠中被钝化。总而言之，这些数据表明，AT1-R上的Ang-(1-7)天然偏向激动剂可以微调肾素-血管紧张素-醛固酮系统的生理。
Hyperactivity of the renin-angiotensin-aldosterone system through the angiotensin II (Ang II)/Ang II type 1 receptor (AT1-R) axis constitutes a hallmark of hypertension. Recent findings indicate that only a subset of AT1-R signaling pathways is cardiodeleterious, and their selective inhibition by biased ligands promotes therapeutic benefit. To date, only synthetic biased ligands have been described, and whether natural renin-angiotensin-aldosterone system peptides exhibit functional selectivity at AT1-R remains unknown. In this study, we systematically determined efficacy and potency of Ang II, Ang III, Ang IV, and Ang-(1-7) in AT1-R-expressing HEK293T cells on the activation of cardiodeleterious G-proteins and cardioprotective -arrestin2. Ang III and Ang IV fully activate similar G-proteins than Ang II, the prototypical AT1-R agonist, despite weaker potency of Ang IV. Interestingly, Ang-(1-7) that binds AT1-R fails to promote G-protein activation but behaves as a competitive antagonist for Ang II/Gi and Ang II/Gq pathways. Conversely, all renin-angiotensin-aldosterone system peptides act as agonists on the AT1-R/-arrestin2 axis but display biased activities relative to Ang II as indicated by their differences in potency and AT1-R/-arrestin2 intracellular routing. Importantly, we reveal Ang-(1-7) a known Mas receptor-specific ligand, as an AT1-R-biased agonist, selectively promoting -arrestin activation while blocking the detrimental Ang II/AT1-R/Gq axis. This original pharmacological profile of Ang-(1-7) at AT1-R, similar to that of synthetic AT1-R-biased agonists, could, in part, contribute to its cardiovascular benefits. Accordingly, in vivo, Ang-(1-7) counteracts the phenylephrine-induced aorta contraction, which was blunted in AT1-R knockout mice. Collectively, these data suggest that Ang-(1-7) natural-biased agonism at AT1-R could fine-tune the physiology of the renin-angiotensin-aldosterone system.