Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo.
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.
Ishida
Junji
J
Center for Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, Institute of Basic Medical Sciences, Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
Hashimoto
Tatsuo
T
Hashimoto
Yasumi
Y
Nishiwaki
Shiro
S
Iguchi
Taku
T
Harada
Shuichi
S
Sugaya
Takeshi
T
Matsuzaki
Hitomi
H
Yamamoto
Rie
R
Shiota
Naotaka
N
Okunishi
Hideki
H
Kihara
Minoru
M
Umemura
Satoshi
S
Sugiyama
Fumihiro
F
Yagami
Ken-Ichi
K
Kasuya
Yoshitoshi
Y
Mochizuki
Naoki
N
Fukamizu
Akiyoshi
A
D000483:Alleles; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000075244:Apelin Receptors; D001794:Blood Pressure; D015152:Blotting, Northern; D018076:DNA, Complementary / Q000378:metabolism; D004727:Endothelium / Q000201:enzymology; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008957:Models, Genetic; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism / Q000502:physiology*; D011995:Recombination, Genetic; D012694:Serine / Q000737:chemistry; D013997:Time Factors
C104575:APLNR protein, human; D000075244:Apelin Receptors; C491285:Aplnr protein, mouse; C491284:Aplnr protein, rat; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D012694:Serine; D012313:RNA; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester