The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism

Tatemoto, Kazuhiko; Takayama, Kiyoshige; Zou, Min‐Xu; Kumaki, Iku; Zhang, Wei; Kumano, K; Fujimiya, Mineko

doi:10.1016/s0167-0115(01)00236-1

Cited by 576 publications

(486 citation statements)

References 17 publications

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“…Results are representative of those obtained from three independent experiments. localization of apelin expression in tissues was observed in vascular endothelial cells (ECs), adipose tissue and epithelial cells, suggesting a role for apelin/APJ in angiogenesis and vascular formation [18,19]. Similarly, location of APJ is very important for Apelin/APJ signaling pathway to exert physiological function in various cells and tissues [20].…”

Section: Discussionmentioning

confidence: 99%

Apelin activates the expression of inflammatory cytokines in microglial BV2 cells via PI-3K/Akt and MEK/Erk pathways

Chen

Tao

Jiang

2015

Sci. China Life Sci.

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Section: Discussionmentioning

confidence: 99%

Apelin activates the expression of inflammatory cytokines in microglial BV2 cells via PI-3K/Akt and MEK/Erk pathways

Chen

Tao

Jiang

2015

Sci. China Life Sci.

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“…Apelin-36 was the first of these shorter C-terminal sequences being described to bind and activate APJ [45]. Also Apelin-17, Apelin-13 and its pyroglutamyl isoform which is resistant to degradation, (Pyr1)-Apelin-13, were proven to act as functional ligands of APJ and in some cases exhibited much higher biological activity than Apelin-36 [45,17,18,25,46].…”

Section: Introductionmentioning

confidence: 99%

The apelinergic system in the developing lung: Expression and signaling

et al. 2011

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a b s t r a c tApelin and its receptor APJ constitute a signaling pathway best recognized as an important regulator of cardiovascular homeostasis. This multifunctional peptidergic system is currently being described to be involved in embryonic events which extend into vascular, ocular and heart development. Additionally, it is highly expressed in pulmonary tissue. Therefore, the aim of this study was to investigate the role of apelinergic system during fetal lung development. Immunohistochemistry and Western blot analysis were used to characterize apelin and APJ expression levels and cellular localization in normal fetal rat lungs, at five different gestational ages as well as in the adult. Fetal rat lung explants were cultured in vitro with increasing doses of apelin. Treated lung explants were morphometrically analyzed and assessed for MAPK signaling modifications. Both components of the apelinergic system are constitutively expressed in the developing lung, with APJ exhibiting monomeric, dimeric and oligomeric forms in the pulmonary tissue. Pulmonary epithelium also displayed constitutive nuclear localization of the receptor. Fetal apelin expression is higher than adult expression. Apelin supplementation inhibitory effect on branching morphogenesis was associated with a dose dependent decrease in p38 and JNK phosphorylation. The results presented provide the first evidence of the presence of an apelinergic system operating in the developing lung. Our findings also suggest that apelin inhibits fetal lung growth by suppressing p38 and JNK signaling pathways.

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“…Intravenous administration of apelin suggested a hypotensive effect in rat (5,(7)(8)(9). On the other hand, apelin potently contracts human saphenous vein smooth muscle cells in vitro (10), indicating that apelin is a potent vasoconstrictor.…”

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confidence: 99%

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

Ishida

Hashimoto

et al. 2004

Journal of Biological Chemistry

367

294

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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...

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The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism

Cited by 576 publications

References 17 publications

Apelin activates the expression of inflammatory cytokines in microglial BV2 cells via PI-3K/Akt and MEK/Erk pathways

Apelin activates the expression of inflammatory cytokines in microglial BV2 cells via PI-3K/Akt and MEK/Erk pathways

The apelinergic system in the developing lung: Expression and signaling

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

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