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首页> 外文期刊>Circulation research: a journal of the American Heart Association >Discovery and characterization of alamandine: A novel component of the renin-angiotensin system
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Discovery and characterization of alamandine: A novel component of the renin-angiotensin system

机译：阿拉曼丁的发现与表征：肾素-血管紧张素系统的新组成部分

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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 β-alanine and PD123319, but not by the Mas antagonist A-779. In addition, oral administration of an inclusion compound of alamandine/β-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.
机译：理由：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剂。在这里，我们报告鉴定和表征alamandine，由血管紧张素转换酶2血管紧张素A或直接从血管紧张素-（1-7）的催化作用产生的一种新的七肽。目的：表征RAS的一种新型成分，阿拉曼丁。方法和结果：使用质谱法我们观察到，金刚烷胺在人的血液中循环，可以由心脏中的血管紧张素（1-7）形成。 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，降压和中枢作用。有趣的是，我们的数据显示其作用独立于RAS，Mas和2型血管紧张素II受体的已知血管扩张剂受体。相反，我们证明了金刚烷胺通过与Mas相关的G蛋白偶联受体D起作用。金刚烷胺与Mas相关的G蛋白偶联受体D的结合被D-Pro7-血管紧张素-（1- 7），与Mas相关的G蛋白偶联受体，成员D配体β-丙氨酸和PD123319，但不是由Mas拮抗剂A-779引起的。另外，口服给予金刚烷胺/β-羟丙基环糊精的包合物可在自发性高血压大鼠中产生长期的降压作用，并在经异丙肾上腺素治疗的大鼠中产生抗纤维化作用。 Alamandine在人肿瘤细胞系中没有明显的增殖或抗增殖作用。结论：对这两种新的RAS成分，阿拉曼丁及其受体的鉴定，为了解RAS的生理和病理生理作用提供了新的见解，并可能有助于开发治疗人类心血管疾病和其他相关疾病的新治疗策略。

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