Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo
Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo
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DOI：
10.1074/jbc.m404149200
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发表时间：
2004-06-18
影响因子：
4.8
通讯作者：
Fukamizu, A
中科院分区：
文献类型：
--
作者：
Ishida, J;Hashimoto, T;Fukamizu, A
APJ是一种具有7个跨膜结构域的G蛋白偶联受体，其内源性配体apelin是最近发现的。它们在心血管系统中高度表达，表明APJ在血压调节中很重要。为了研究APJ的生理功能，我们已经产生了缺乏编码APJ的基因的小鼠。在稳态下，APJ缺陷型小鼠的基线血压与野生型小鼠相当。施用爱帕琳肽短暂降低了野生型小鼠和高血压模型动物（自发性高血压大鼠）的血压。另一方面，这种对apelin的过度反应在APJ缺陷小鼠中被消除。这种apelin诱导的反应被抑制预处理与一氧化氮合酶抑制剂，apelin诱导的磷酸化的内皮一氧化氮合酶在肺内皮细胞从APJ缺陷小鼠消失。此外，APJ缺陷小鼠表现出对最有效的血管收缩剂血管紧张素II的升压反应增加，与血管紧张素1a型受体缺陷小鼠相比，APJ和血管紧张素1a型受体纯合子的双突变小鼠的基线血压显著升高。这些结果表明，APJ在体内发挥了降压作用，并对血管紧张素II的升压作用起反调节作用。
APJ is a G-protein-coupled receptor with seven transmembrane domains, and its endogenous ligand, apelin, was identified recently. They are highly expressed in the cardiovascular system, suggesting that APJ is important in the regulation of blood pressure. To investigate the physiological functions of APJ, we have generated mice lacking the gene encoding APJ. The base-line blood pressure of APJ-deficient mice is equivalent to that of wild-type mice in the steady state. The administration of apelin transiently decreased the blood pressure of wild-type mice and a hypertensive model animal, a spontaneously hypertensive rat. On the other hand, this hypotensive response to apelin was abolished in APJ-deficient mice. This apelin-induced response was inhibited by pretreatment with a nitric-oxide synthase inhibitor, and apelin-induced phosphorylation of endothelial nitric-oxide synthase in lung endothelial cells from APJ-deficient mice disappeared. In addition, APJ-deficient mice showed an increased vasopressor response to the most potent vasoconstrictor angiotensin II, and the base-line blood pressure of double mutant mice homozygous for both APJ and angiotensin-type 1a receptor was significantly elevated compared with that of angiotensin-type 1a receptor-deficient mice. These results demonstrate that APJ exerts the hypotensive effect in vivo and plays a counterregulatory role against the pressor action of angiotensin II.