活化的爱帕琳受体的扩张作用与\b{eta} -抑制蛋白募集相关
The hypotensive effect of activated apelin receptor is correlated with \b{eta}-arrestin recruitment
摘要：
apelinergic系统是调节血管张力和心血管功能的重要参与者，使该生理系统成为高血压、心力衰竭和缺血性心脏病药物开发的有吸引力的靶点。事实上，爱帕琳在人体中发挥正性肌力作用，同时降低外周血管阻力。在这项研究中，我们调查了信号通路通过爱帕琳发挥其治疗作用。我们合成了一系列爱帕琳-13类似物，其中C-末端Phe 13残基被天然或非天然氨基酸取代。在表达APJ的HEK 293细胞中，我们评价了这些化合物激活Gαi1和GαoA G蛋白、募集\b{eta} -抑制蛋白1和2（\b{eta} arrs）以及抑制cAMP生成的相对功效。计算每个通路的转导率使我们能够鉴定出具有不同信号传导谱的几种类似物。此外，我们发现这些类似物静脉注射给Sprague-Dawley大鼠产生了广泛的肿胀反应。事实上，两种化合物失去了降低血压的能力，而其他类似物则像apelin-13一样显著降低血压。有趣的是，不降低血压的类似物在招募\b{eta} arrs方面效果较差。最后，使用Spearman相关性，我们确定了肿胀反应与\b{eta}募集显著相关，但与G蛋白依赖性信号传导无关。总之，我们的结果表明，\b{eta}的细胞募集能力与活化的APJ的消肿功效有关。
英文摘要：
The apelinergic system is an important player in the regulation of both vascular tone and cardiovascular function, making this physiological system an attractive target for drug development for hypertension, heart failure and ischemic heart disease. Indeed, apelin exerts a positive inotropic effect in humans whilst reducing peripheral vascular resistance. In this study, we investigated the signaling pathways through which apelin exerts its hypotensive action. We synthesized a series of apelin-13 analogs whereby the C-terminal Phe13 residue was replaced by natural or unnatural amino acids. In HEK293 cells expressing APJ, we evaluated the relative efficacy of these compounds to activate Gαi1 and GαoA G-proteins, recruit \b{eta}-arrestins 1 and 2 (\b{eta}arrs), and inhibit cAMP production. Calculating the transduction ratio for each pathway allowed us to identify several analogs with distinct signaling profiles. Furthermore, we found that these analogs delivered i.v. to Sprague-Dawley rats exerted a wide range of hypotensive responses. Indeed, two compounds lost their ability to lower blood pressure, while other analogs significantly reduced blood pressure as apelin-13. Interestingly, analogs that did not lower blood pressure were less effective at recruiting \b{eta}arrs. Finally, using Spearman correlations, we established that the hypotensive response was significantly correlated with \b{eta}arr recruitment but not with G protein- dependent signaling. In conclusion, our results demonstrated that the \b{eta}arr recruitment potency is involved in the hypotensive efficacy of activated APJ.
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