Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely

Sun, Xiao; Iida, Shinichiro; Yoshikawa, A.; Senbonmatsu, Rina; Imanaka, Kazuhito; Maruyama, Kei; Nishimura, Shigeyuki; Inagami, Tadashi; Senbonmatsu, Takaaki

doi:10.1038/hr.2011.19

Cited by 37 publications

(35 citation statements)

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“…APJ and AT1 receptor-receptor interactions are presently accounted as the potential molecular mechanism of crosstalk responsible for this reciprocal counter-regulation between apelin and Ang II pathways, since it was observed in vitro that the respective receptors can form heterodimers and that this heterodimerisation influences downstream signaling [7]. Our observations on fetal lung growth are in accordance with others reporting that the proposed effects of the apelin-APJ system are opposite to those of the Ang II-AT1 receptor pathway [7,44].…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

The apelinergic system in the developing lung: Expression and signaling

et al. 2011

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“…The AT1R/APJ interaction described here provides a glimpse into the true allosteric nature of receptor heterodimers, in that depending on how they are arranged, striking asymmetries may be detected in how each protomer interacts with ligands and further, how it might signal in a manner distinct from the parent monomeric or homodimeric receptors. Previous studies have demonstrated that activated APJ modulates AT1R signalling in HEK 293 cells (Sun et al, 2011) and in primary vascular smooth muscle cells (Chun et al, 2008;Siddiquee et al, 2011). In one study, there were striking differences detected in the effects of unoccupied and ligand-occupied APJ on AT1R signalling, suggesting distinct allosteric interactions depending on the state of the system (Sun et al, 2011).…”

Section: At1r Are Social Animals-they Interact With Other Gpcrsmentioning

confidence: 99%

“…Such regulation likely depends on the relative abundance of the two receptors in a given tissue. Indeed, others have shown the AT1R is likely to be a signalling hub whose functions are controlled by a number of partner receptors such as the b2AR (Barki-Harrington et al, 2003), the B2 bradykinin receptor (Quitterer et al, 2004) and the apelin receptor (Chun et al, 2008;Siddiquee et al, 2011;Sun et al, 2011).…”

Section: At1r Are Social Animals-they Interact With Other Gpcrsmentioning

confidence: 99%

GPCR heterodimers: asymmetries in ligand binding and signalling output offer new targets for drug discovery

Goupil

Laporte

Hébert

2013

British J Pharmacology

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Dimers of GPCRs have held the imagination of researchers for almost 20 years. However, only recently has their value as potentially novel drug targets been increased significantly, and primarily, in the context of GPCR heterodimers. The view of receptor heterodimers as allosteric machines has transformed the way we understand structural and functional asymmetries inherent in their organization. These asymmetries alter both signalling output and how they might be targeted pharmacologically. The paper in this issue of BJP by Siddiquee and colleagues (2013) highlights our growing understanding of such asymmetries and their implications. They show that heterodimers of the angiotensin II AT1 receptor and the apelin receptor recognize and respond to their respective ligands in distinct ways from the parent receptors expressed alone. Further, they demonstrate asymmetric allosteric effects in the context of the heterodimer that may have significant implications for our understanding of such receptor complexes.

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“…By contrast, it has been proposed that inactivated APJ can form heterodimers with AT1 which suppresses RAS signalling. This inhibitory effect is reduced by the binding of apelin to APJ [33]. In addition to the modulation on AT1R signalling, apelin counteracts RAS by up-regulating ACE2 expression via APJ (Fig.…”

Section: Apelin/apj System Vs Renin-angiotensin System (Ras)mentioning

confidence: 99%

Effects of apelin on the cardiovascular system

et al. 2015

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Apelin is an endogenous peptide acting on the APJ receptor. It consists of several isoforms characterised by different numbers of aminoacids. The number of aminoacids in the active isoforms range from 36 to 12. Apelin-13 and, to a lesser extent, apelin-36 are considered the most active isoforms with the greatest activity on the cardiovascular homeostasis. The effects normally exerted by the basal level of endogenous apelin, can be enhanced not only by its up-regulation, but may also by its exogenous administration. The present review considers the effects of apelin on various aspects of the cardiovascular function, such as cardiac development, vasomotor tone, angiogenesis, myocardial inotropy in healthy and failing hearts as well as the prevention of ischemia-reperfusion injury, cardiac fibrosis and remodeling. Also the biphasic changes of apelin level during the evolution of heart failure are considered. Although the positive inotropic effect exerted by apelin in normal and failing hearts would suggest the use of this peptide in the treatment of heart failure, the limited duration and extent of its effect do not support this possibility, unless a long lasting (6 hours) infusion is performed to overcome the limit of its short life. However, although the data on the characteristics of the inotropic activity do not provide a strong support for the treatment of active heart failure, apelin may be used in the prevention of heart failure because of its activity in limiting the consequences of myocardial ischemia such as infarct size and cardiac remodeling. KeywordsApelin/APJ system, heart failure, ischemia-reperfusion injury, contractility, cardiac protection, Reninangiotensin system 2 The apelin/APJ system Apelin In 1998 Tatemoto et al. discovered the endogenous peptide capable of binding the G protein-coupled receptor (GPCR) APJ [1,2], which at that time was considered an orphan receptor becaue its ligand was unknown. The just discovered ligand was called, apelin e.g APj Endogenous LIgaNd. Apelin is expressed in hearts, lungs, kidneys, liver, adipose tissue, gastrointestinal tract, brain, adrenal glands, endothelium, and human plasma. The gene of apelin is located on chromosome X [3] and encodes a 77 aminoacid sequence called pre-pro-apelin [4]. Upon cleavage by a family of endopeptidases, pre-pro-apelin generates several C-terminal fragments of various size, which are classified on the basis of the number of aminoacids. The active isoforms range from 36 to 12 aminoacids. As fragments shorter than 12 aminoacids are biologically inactive, it appears evident that the Cterminal 12 aminoacids are essential for receptor binding, whereas the N-terminal sequence modulates the interaction with the receptor [5]. At present it is recognized that, although different isoforms display similar functions, active isoforms differ in tissue distribution, potency and receptor binding affinity [6]. Apelin-13 and, to a lesser extent, apelin-36 have been considered the most active isoforms with the greatest activity on the cardi...

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Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely

Cited by 37 publications

References 36 publications

The apelinergic system in the developing lung: Expression and signaling

The apelinergic system in the developing lung: Expression and signaling

GPCR heterodimers: asymmetries in ligand binding and signalling output offer new targets for drug discovery

Effects of apelin on the cardiovascular system

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