Discovery and Characterization of Alamandine A Novel Component of the Renin-Angiotensin System
Discovery and Characterization of Alamandine A Novel Component of the Renin-Angiotensin System
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DOI：
10.1161/circresaha.113.301077
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发表时间：
2013-04-12
影响因子：
20.1
通讯作者：
Santos, Robson A. S.
中科院分区：
文献类型：
--
作者：
Lautner, Roberto Queiroga;Villela, Daniel C.;Santos, Robson A. S.
原理：肾素-血管紧张素系统（RAS）是心血管系统、电解质和水平衡的关键调节因子。在这里，我们报告的鉴定和表征alamandine，一个新的七肽产生的血管紧张素转换酶-2血管紧张素A的催化作用或直接从血管紧张素-（1-7）。目的：表征的RAS，alamandine.Methods和结果：使用质谱分析，我们观察到alamandine在人体血液中循环，可以形成从血管紧张素-（1-7）在心脏。Alamandine产生几种类似于血管紧张素-（1-7）产生的生理作用，包括血管舒张、抗纤维化、抗高血压和中枢作用。有趣的是，我们的数据表明，它的行动是独立的RAS，Mas和血管紧张素II 2型受体的已知血管舒张剂受体。相反，我们证明阿拉曼丁通过Mas相关的G蛋白偶联受体（成员D）发挥作用。Alamandine与Mas相关G蛋白偶联受体D成员的结合被D-Pro 7-血管紧张素-（1-7）（Mas相关G蛋白偶联受体D成员配体β-丙氨酸和PD 123319）阻断，但不被Mas拮抗剂A-779阻断。此外，口服阿拉曼丁/β-羟丙基环糊精包合物对自发性高血压大鼠产生了长期降压作用，对异丙肾上腺素治疗的大鼠产生了抗纤维化作用。Alamandine在人肿瘤细胞株中没有明显的增殖或抗增殖作用。结论：这两个新的RAS，Alamandine及其受体的组成部分的鉴定，为理解RAS的生理和病理生理作用提供了新的见解，并可能有助于开发新的治疗策略，用于治疗人类心血管疾病和其他相关疾病。(Circ 2013; 112：1104-1111）。
Rationale: The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1-7).Objective: To characterize a novel component of the RAS, alamandine.Methods and Results: Using mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. Binding of alamandine to Mas-related G-protein-coupled receptor, member D is blocked by D-Pro7-angiotensin-(1-7), the Mas-related G-protein-coupled receptor, member D ligand beta-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/beta-hydroxypropyl cyclodextrin produced a long-term antihypertensive effect in spontaneously hypertensive rats and antifibrotic effects in isoproterenol-treated rats. Alamandine had no noticeable proliferative or antiproliferative effect in human tumoral cell lines.Conclusions: The identification of these 2 novel components of the RAS, alamandine and its receptor, provides new insights for the understanding of the physiological and pathophysiological role of the RAS and may help to develop new therapeutic strategies for treating human cardiovascular diseases and other related disorders. (Circ Res. 2013; 112: 1104-1111.)