Regulatory Roles for APJ, a Seven-transmembrane Receptor Related to Angiotensin-type 1 Receptor in Blood Pressure in Vivo

Abstract

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 apelininduced 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 angiotensintype 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.A family of G protein-coupled receptors bind a large variety of ligands and plays an essential role for physiological functions in vivo including the maintenance of homeostasis in the cardiovascular system. APJ (a putative receptor protein related to the angiotensin-type 1 receptor (AT1)) 1 is a G protein-coupled receptor that was isolated from human genomic DNA using the polymerase chain reaction (1). The APJ has a 31% amino acid sequence homology with the AT1, but APJ does not display specific binding for angiotensin II, which is the ligand of AT1 and exerts a pressor action in the blood pressure regulation (1). Recently, the endogenous ligand of APJ was identified from bovine stomach, and this peptide was named apelin (for APJ endogenous ligand) (2). APJ and apelin are expressed in several tissues including the cardiovascular and the central nervous systems (3-6), and the structure of APJ and apelin is highly conserved among species, suggesting its important physiological roles.Intravenous administration of apelin suggested a hypotensive effect in rat (5, 7-9). On the other hand, apelin potently contracts human saphenous vein smooth muscle cells in vitro (10), indicating that apelin is a potent vasoconstrictor. Thus, at this moment, the action of apelin in blood pressure regulation is controversial, and it is still unclear whether these actions of apelin are really through APJ because of the absence of specific receptor blocker to clarify the in vivo functions of APJ. Therefore, in this study, by using animal models such as APJ-deficient mice, APJ/AT1a double knock-out mice, and spontaneously hypertens...

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

“…) was observed in isolated mouse endothelial cells (Ishida et al 2004). In the isolated rat aorta, apelin stimulates the transport of L-arginine and enhances the activity of eNOS to stimulate the production of nitric oxide (Jia et al 2007), while post-infarct treatment of rats with (Pyr 1 )apelin-13 significantly increases serum nitric oxide levels (Azizi et al 2013).…”

“…However, experiments carried out in animal models have yielded conflicting results about the role of peripheral apelin in the regulation of vascular tone, with both pressor and depressor responses being described , Ishida et al 2004. In anaesthetised intact rats, the overall effect of peripherally administered apelin is the reduction of MABP , Reaux et al 2001, Tatemoto et al 2001, Cheng et al 2003.…”

“…Importantly, the RAS plays a critical role in the pathogenesis of heart failure (Kim & Iwao 2000). Interestingly, apelin exerts many physiological effects that appear to oppose those exerted by Ang II (Tatemoto et al 2001, Chen et al 2003, Cheng et al 2003, Ishida et al 2004, Lee et al 2006. More recently, apelin has been shown to block many Ang II-initiated processes, perhaps partly by dimerisation between APJ and AT 1 .…”

“…Further evidence that APJ plays a role in the regulation of BP comes from a study on mice with a global deletion of APJ, where a transient decrease in systolic BP observed in conscious wild-type (WT) mice following i.p. injection of (Pyr 1 )apelin-13 is abolished in APJ KO mice (Ishida et al 2004). However, while peripheral apelin is a vasodilator in the human saphenous vein, in vessels denuded of endothelium, apelin acts as a vasoconstrictor (Katugampola et al 2001.…”

The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice

“…Apelin also increases drinking behavior (14) and reduces food intake (17) in model experiments in rodents. Furthermore, mice with null mutation of the apj receptor gene exhibit increased vasopressor response to angiotensin II as suggestive of counter-regulation of the apj and angiotensin II receptors (18).…”