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Anthony P. Davenport - One of the best experts on this subject based on the ideXlab platform.
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international union of basic and clinical pharmacology cvii structure and pharmacology of the Apelin receptor with a recommendation that elabela toddler is a second endogenous peptide ligand
Pharmacological Reviews, 2019Co-Authors: Cai Read, Robyn Macrae, Duuamene Nyimanu, Janet J. Maguire, Peiran Yang, Robert C. Glen, Thomas L. Williams, David J Huggins, Petra Sulentic, Anthony P. DavenportAbstract:The predicted protein encoded by the APJ gene discovered in 1993 was originally classified as a class A G protein-coupled orphan receptor but was subsequently paired with a novel peptide ligand, Apelin-36 in 1998. Substantial research identified a family of shorter peptides activating the Apelin receptor, including Apelin-17, Apelin-13, and [Pyr1]Apelin-13, with the latter peptide predominating in human plasma and cardiovascular system. A range of pharmacological tools have been developed, including radiolabeled ligands, analogs with improved plasma stability, peptides, and small molecules including biased agonists and antagonists, leading to the recommendation that the APJ gene be renamed APLNR and encode the Apelin receptor protein. Recently, a second endogenous ligand has been identified and called Elabela/Toddler, a 54-amino acid peptide originally identified in the genomes of fish and humans but misclassified as noncoding. This precursor is also able to be cleaved to shorter sequences (32, 21, and 11 amino acids), and all are able to activate the Apelin receptor and are blocked by Apelin receptor antagonists. This review summarizes the pharmacology of these ligands and the Apelin receptor, highlights the emerging physiologic and pathophysiological roles in a number of diseases, and recommends that Elabela/Toddler is a second endogenous peptide ligand of the Apelin receptor protein.
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Apelin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: Anthony P. Davenport, Duuamene Nyimanu, Janet J. Maguire, Matthias J. Kleinz, Thomas L. Williams, Robyn G. C. Macrae, Peiran YangAbstract:The Apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the Apelin receptor [68]) responds to Apelin, a 36 amino-acid peptide derived initially from bovine stomach. Apelin-36, Apelin-13 and [Pyr1]Apelin-13 are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) by a so far unidentified enzymatic pathway [80]. A second family of peptides discovered independently and named Elabela [11] or Toddler, that has little sequence similarity to Apelin, is present, and functional at the Apelin receptor in the adult cardiovascular system [87, 67]. Structure-activity relationship Elabela analogues have been described [61].
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pyr1 Apelin 13 1 12 is a biologically active ace2 metabolite of the endogenous cardiovascular peptide pyr1 Apelin 13
Frontiers in Neuroscience, 2017Co-Authors: Peiran Yang, Rhoda E. Kuc, Aimee L. Brame, Alex Dyson, Mervyn Singer, Robert C. Glen, Joseph Cheriyan, Ian B. Wilkinson, Anthony P. DavenportAbstract:Aims: Apelin is a predicted substrate for ACE2, a novel therapeutic target. Our aim was to demonstrate the endogenous presence of the putative ACE2 product [Pyr1]Apelin-13(1-12) in human cardiovascular tissues and to confirm it retains significant biological activity for the Apelin receptor in vitro and in vivo. The minimum active Apelin fragment was also investigated. Methods and Results: [Pyr1]Apelin-13 incubated with recombinant human ACE2 resulted in de novo generation of [Pyr1]Apelin-13(1-12) identified by mass spectrometry. Endogenous [Pyr1]Apelin-13(1-12) was detected by immunostaining in human heart and lung localized to the endothelium. Expression was undetectable in lung from patients with pulmonary arterial hypertension. In human heart [Pyr1]Apelin-13(1-12) (pKi = 8.04±0.06) and Apelin-13(F13A) (pKi = 8.07±0.24) competed with [125I]Apelin-13 binding with nanomolar affinity, 4-fold lower than for [Pyr1]Apelin-13 (pKi = 8.83±0.06) whereas Apelin-17 exhibited highest affinity (pKi = 9.63±0.17). The rank order of potency of peptides to inhibit forskolin-stimulated cAMP was Apelin-17 (pD2 = 10.31±0.28) > [Pyr1]Apelin-13 (pD2 = 9.67±0.04) Apelin-13(F13A) (pD2 = 9.54±0.05) > [Pyr1]Apelin-13(1-12) (pD2 = 9.30±0.06). The truncated peptide Apelin-13(R10M) retained nanomolar potency (pD2 = 8.70±0.04) but shorter fragments exhibited low micromolar potency. In a β-arrestin recruitment assay the rank order of potency was Apelin-17 (pD2 = 10.26±0.09) >> [Pyr1]Apelin-13 (pD2 = 8.43±0.08) > Apelin-13(R10M) (pD2 = 8.26±0.17) > Apelin-13(F13A) (pD2 = 7.98±0.04) [Pyr1]Apelin-13(1-12) (pD2 = 7.84±0.06) >> shorter fragments (pD2<6). [Pyr1]Apelin-13(1-12) and Apelin-13(F13A) contracted human saphenous vein with similar sub-nanomolar potencies and [Pyr1]Apelin-13(1-12) was a potent inotrope in paced mouse right ventricle and human atria. [Pyr1]Apelin-13(1-12) elicited a dose-dependent decrease in blood pressure in anaesthetized rat and dose-dependent increase in forearm blood flow in human volunteers. Conclusions: We provide evidence that ACE2 cleaves [Pyr1]Apelin-13 to [Pyr1]Apelin-13(1-12) and this cleavage product is expressed in human cardiovascular tissues. We have demonstrated biological activity of [Pyr1]Apelin-13(1-12) at the human and rodent Apelin receptor in vitro and in vivo. Our data show that reported enhanced ACE2 activity in cardiovascular disease should not significantly compromise the beneficial effects of Apelin based therapies for example in PAH.
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abstract 13911 elabela toddler apela is an endogenous ligand of the human Apelin receptor and is reduced in pulmonary arterial hypertension
Circulation, 2015Co-Authors: Peiran Yang, Rhoda E. Kuc, Janet J. Maguire, Mark Southwood, Nicholas W. Morrell, Anthony P. DavenportAbstract:Introduction: The Apelin receptor is proposed as a therapeutic target in pulmonary arterial hypertension (PAH). The Apelin peptide knockout mouse does not recapitulate the Apelin receptor knockout ...
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pyr1 Apelin 13 identified as the predominant Apelin isoform in the human heart vasoactive mechanisms and inotropic action in disease
Hypertension, 2009Co-Authors: Janet J. Maguire, Matthias J. Kleinz, Sarah L Pitkin, Anthony P. DavenportAbstract:Apelin receptors, present on vascular smooth muscle cells, endothelium, and cardiomyocytes, are activated by the family of Apelin peptides to elicit cardiovascular effects in experimental animals, but functional activity in humans has not been studied in detail. We detected low levels of Apelin immunoreactivity in plasma of volunteers consistent with an autocrine/paracrine action and detected Apelin immunoreactivity in the supernatant from human cultured endothelial cells. We found that [Pyr(1)]Apelin-13 was the predominant isoform in cardiac tissue from patients with coronary artery disease. We tested the hypothesis that Apelins have vascular and cardiac actions in human tissues in vitro and compared responses to [Pyr(1)]Apelin-13, Apelin-13, and Apelin-36. In endothelium-intact mammary artery, all 3 of the Apelins induced concentration-dependent vasodilatation with comparable potency (EC(50): 0.6 to 1.6 nM; maximum response: 40% to 50%). Vasodilatation was abolished after endothelial removal or preincubation with indomethacin but was unaffected by preincubation with N(G)-nitro-L-arginine methyl ester, indicating involvement of prostanoids but not NO in dilatation by Apelins in this patient group. Apelins were potent constrictors of endothelium-denuded saphenous vein (EC(50): 0.6 to 1.6 nM; maximum response: 17% to 26%) and mammary artery ([Pyr(1)]Apelin-13; EC(50): 0.2 nM; maximum response: 29%). In paced atrial strips, all 3 of the peptides increased the force of contraction with subnanomolar potencies (EC(50): 40 to 125 pM). For the first time, we demonstrate that the 3 principal forms of Apelin have comparable potency and efficacy in human cardiovascular tissues. Apelins are potent endothelium-dependent vasodilators acting via a prostanoid-dependent mechanism; however, removal of the endothelium revealed direct vasoconstrictor actions in both the artery and vein. Furthermore, in human cardiac tissue, the Apelin peptides are among the most potent endogenous positive inotropic agents yet reported.
Cedric Dray - One of the best experts on this subject based on the ideXlab platform.
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The intestinal glucose-Apelin cycle controls carbohydrate absorption in mice.
Gastroenterology, 2013Co-Authors: Cedric Dray, Daniele Daviaud, Yassine Sakar, Claire Vinel, Bernard Masri, Luc Garrigues, Estelle Wanecq, Sylvain Galvani, Anne Negre-salvayre, Larry BarakAbstract:BACKGROUND & AIMS: Glucose is absorbed into intestine cells via the sodium glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2); various peptides and hormones control this process. Apelin is a peptide that regulates glucose homeostasis and is produced by proximal digestive cells; we studied whether glucose modulates Apelin secretion by enterocytes and the effects of Apelin on intestinal glucose absorption. METHODS: We characterized glucose-related luminal Apelin secretion in vivo and ex vivo by mass spectroscopy and immunologic techniques. The effects of Apelin on (14)C-labeled glucose transport were determined in jejunal loops and in mice following Apelin gavage. We determined levels of GLUT2 and SGLT-1 proteins and phosphorylation of AMPKα2 by immunoblotting. The net effect of Apelin on intestinal glucose transepithelial transport was determined in mice. RESULTS: Glucose stimulated luminal secretion of the pyroglutaminated Apelin-13 isoform ([Pyr-1]-Apelin-13) in the small intestine of mice. Apelin increased specific glucose flux through the gastric epithelial barrier in jejunal loops and in vivo following oral glucose administration. Conversely, pharmacologic Apelin blockade in the intestine reduced the increased glycemia that occurs following oral glucose administration. Apelin activity was associated with phosphorylation of AMPKα2 and a rapid increase of the GLUT2/SGLT-1 protein ratio in the brush border membrane. CONCLUSIONS: Glucose amplifies its own transport from the intestinal lumen to the bloodstream by increasing luminal Apelin secretion. In the lumen, active Apelin regulates carbohydrate flux through enterocytes by promoting AMPKα2 phosphorylation and modifying the ratio of SGLT-1:GLUT2. The glucose-Apelin cycle might be pharmacologically handled to regulate glucose absorption and assess better control of glucose homeostasis.
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Apelin treatment increases complete Fatty Acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice.
Diabetes, 2012Co-Authors: Camille Attane, Cedric Dray, Daniele Daviaud, Estelle Wanecq, Camille Foussal, Sophie Le Gonidec, Alexandre Benani, Rocío Guzmán-ruiz, Veronic Bezaire, Chloé RancouleAbstract:Both acute and chronic Apelin treatment have been shown to improve insulin sensitivity in mice. However, the effects of Apelin on fatty acid oxidation (FAO) during obesity-related insulin resistance have not yet been addressed. Thus, the aim of the current study was to determine the impact of chronic treatment on lipid use, especially in skeletal muscles. High-fat diet (HFD)-induced obese and insulin-resistant mice treated by an Apelin injection (0.1 μmol/kg/day i.p.) during 4 weeks had decreased fat mass, glycemia, and plasma levels of triglycerides and were protected from hyperinsulinemia compared with HFD PBS-treated mice. Indirect calorimetry experiments showed that Apelin-treated mice had a better use of lipids. The complete FAO, the oxidative capacity, and mitochondrial biogenesis were increased in soleus of Apelin-treated mice. The action of Apelin was AMP-activated protein kinase (AMPK) dependent since all the effects studied were abrogated in HFD Apelin-treated mice with muscle-specific inactive AMPK. Finally, the Apelin-stimulated improvement of oxidative capacity led to decreased levels of acylcarnitines and enhanced insulin-stimulated glucose uptake in soleus. Thus, by promoting complete lipid use in muscle of insulin-resistant mice through mitochondrial biogenesis and tighter matching between FAO and the tricarboxylic acid cycle, Apelin treatment could contribute to insulin sensitivity improvement.
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Apelin and apj regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans
American Journal of Physiology-endocrinology and Metabolism, 2010Co-Authors: Cedric Dray, Daniele Daviaud, Cyrille Debard, Jennifer Jager, Emmanuel Disse, Pascal G P Martin, Camille AttaneAbstract:Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of Apelin and APJ (Apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied Apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, Apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/db mice. In skeletal muscle, Apelin expression was similar in control and HF-fed mice and decreased in db/db mice. APJ expression was decreased in both HF-fed and db/db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal Apelin and APJ expression in AT and muscle between control and diabetic patients. However, Apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased Apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that Apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance.
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Apelin stimulates glucose utilization in normal and obese insulin resistant mice
Cell Metabolism, 2008Co-Authors: Cedric Dray, Claude Knauf, Daniele Daviaud, Jeremie Boucher, Aurelie WagetAbstract:Adipose tissue (AT) secretes several adipokines that influence insulin sensitivity and potentially link obesity to insulin resistance. Apelin, a peptide present in different tissues, is also secreted by adipocytes. Apelin is upregulated in obese and hyperinsulinemic humans and mice. Although a tight relation exists between the regulation of Apelin and insulin, it remains largely unknown whether Apelin affects whole-body glucose utilization. Herein, we show that in chowfed mice, acute intravenous injection of Apelin has a powerful glucose-lowering effect associated with enhanced glucose utilization in skeletal muscle and AT. Through in vivo and in vitro pharmacological and genetic approaches, we demonstrate the involvement of endothelial NO synthase, AMP-activated protein kinase, and Akt in Apelin-stimulated glucose uptake in soleus muscle. Remarkably, in obese and insulin-resistant mice, Apelin restored glucose tolerance and increased glucose utilization. Apelin could thus represent a promising target in the management of insulin resistance.
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effect of hypocaloric diet induced weight loss in obese women on plasma Apelin and adipose tissue expression of Apelin and apj
European Journal of Endocrinology, 2008Co-Authors: Isabelle Castanlaurell, Cedric Dray, Daniele Daviaud, Michaela Vitkova, Michaela Kovacikova, Zuzana Kovacova, J Hejnova, Vladimir Stich, Philippe ValetAbstract:Objective: Apelin is a novel adipokine acting on APJ receptor, regulated by insulin and tumor necrosis factor-a (TNF-a) in adipose tissue (AT). Plasma Apelin levels are increased in obese hyperinsulinemic subjects. The aim was to investigate whether the hypocaloric diet associated with weight loss modifies the elevated plasma Apelin levels and the expression of Apelin and APJ receptor in AT in obese women. Design and methods: Fasting plasma levels of Apelin and TNF-a as well as mRNA levels of Apelin and APJ in AT were measured before and after a 12-week hypocaloric weight-reducing diet in 20 obese women (body mass index (BMI) before diet 32.2G6.4 kg/m 2 ). Twelve healthy women with a BMI of 20.7G 0.6 kg/m 2 served as reference. Results: Plasma levels of Apelin and TNF-a were higher in obese compared with lean controls. The hypocaloric diet resulted in a significant decrease of BMI to 29.8G6.3 kg/m 2 , plasma insulin (8.16G 0.73 to 6.58G0.66 mU/l), Apelin (369G25 pg/ml to 257G12 pg/ml), TNF-a levels (0.66G 0.04 pg/ml to 0.56G0.04 pg/ml), and AT mRNAs of Apelin and APJ. In addition, changes in AT mRNA Apelin were related to changes in AT mRNA APJ levels. Conclusion: The hypocaloric diet associated with weight loss reduces the increased plasma and AT expression of Apelin in obese women. This reduced Apelin expression in AT could contribute to decreased circulating Apelin levels.
Catherine Llorenscortes - One of the best experts on this subject based on the ideXlab platform.
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plasma kallikrein cleaves and inactivates Apelin 17 palmitoyl and peg extended Apelin 17 analogs as metabolically stable blood pressure lowering agents
European Journal of Medicinal Chemistry, 2019Co-Authors: Conrad Fischer, X Iturrioz, Catherine Llorenscortes, Tess Lamer, Wang Wang, Shaun M K Mckinnie, Gavin Y Oudit, John C VederasAbstract:Apelins are human peptide hormones with various physiological activities, including the moderation of cardiovascular, renal, metabolic and neurological function. Their potency is dependent on and limited by proteolytic degradation in the circulatory system. Here we identify human plasma kallikrein (KLKB1) as a protease that cleaves the first three N-terminal amino acids (KFR) of Apelin-17. The cleavage kinetics are similar to neprilysin (NEP), which cleaves within the critical 'RPRL'-motif thereby inactivating Apelin. The resulting C-terminal 14-mer after KLKB1 cleavage has much lower biological activity, and the presence of its N-terminal basic arginine seems to negate the blood pressure lowering effect. Based on C-terminally engineered Apelin analogs (A2), resistant to angiotensin converting enzyme 2 (ACE2), attachment of an N-terminal C16 fatty acid chain (PALMitoylation) or polyethylene glycol chain (PEGylation) minimizes KLKB1 cleavage of the 17-mers, thereby extending plasma half-life while fully retaining biological activity. The N-terminally PEGylated Apelin-17(A2) is a highly protease resistant analog, with excellent Apelin receptor activation and pronounced blood pressure lowering effect.
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angiotensin converting enzyme 2 metabolizes and partially inactivates pyr Apelin 13 and Apelin 17 physiological effects in the cardiovascular system
Hypertension, 2016Co-Authors: Wang Wang, Catherine Llorenscortes, Shaun M K Mckinnie, Maikel Farhan, Manish Paul, Tyler Mcdonald, Brent A Mclean, Saugata Hazra, Allan G Murray, John C VederasAbstract:Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, Apelin peptides have extremely short biological half-lives, and improved understanding of Apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-Apelin 13 and Apelin 17, the dominant Apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-Apelin 13 and Apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-Apelin 13 and Apelin 17 was potentiated, with a corresponding greater elevation in plasma Apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of Apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-Apelin 13 and Apelin 17 efficiently, and Apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of Apelin peptides was further supported by the reduced potency of pyr-Apelin 12 and Apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-Apelin 13 and Apelin 17 rescued contractile function in a myocardial ischemia-reperfusion model, ACE2 cleavage products, pyr-Apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active Apelin analogues that were resistant to ACE2-mediated degradation, thereby confirming that stable Apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of Apelin action in the vasculature and heart.
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Apelin and the proopiomelanocortin system a new regulatory pathway of hypothalamic α msh release
American Journal of Physiology-endocrinology and Metabolism, 2011Co-Authors: Annabelle Reauxle Goazigo, Claude Knauf, Philippe Valet, Laurence Bodineau, Nicolas Chartrel, Nadia Piccode Mota, Lydie Jeandel, Carine Raad, Catherine LlorenscortesAbstract:Neuronal networks originating in the hypothalamic arcuate nucleus (Arc) play a fundamental role in controlling energy balance. In the Arc, neuropeptide Y (NPY)-producing neurons stimulate food intake, whereas neurons releasing the proopiomelanocortin (POMC)-derived peptide α-melanocyte-stimulating hormone (α-MSH) strongly decrease food intake. There is growing evidence to suggest that Apelin and its receptor may play a role in the central control of food intake, and both are concentrated in the Arc. We investigated the presence of Apelin and its receptor in Arc NPY- and POMC-containing neurons and the effects of Apelin on α-MSH release in the hypothalamus. We showed, by immunofluorescence and confocal microscopy, that Apelin-immunoreactive (IR) neuronal cell bodies were distributed throughout the rostrocaudal extent of the Arc and that Apelin was strongly colocalized with POMC, but weakly colocalized with NPY. However, there were numerous NPY-IR nerve fibers close to the Apelin-IR neuronal cell bodies. By combining in situ hybridization with immunohistochemistry, we demonstrated the presence of Apelin receptor mRNA in Arc POMC neurons. Moreover, using a perifusion technique for hypothalamic explants, we demonstrated that Apelin-17 (K17F) increased α-MSH release, suggesting that Apelin released somato-dendritically or axonally from POMC neurons may stimulate α-MSH release in an autocrine manner. Consistent with these data, hypothalamic Apelin levels were found to be higher in obese db/db mice and fa/fa Zucker rats than in wild-type animals. These findings support the hypothesis that central Apelin is involved in regulating body weight and feeding behavior through the direct stimulation of α-MSH release.
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functional dissociation of Apelin receptor signaling and endocytosis implications for the effects of Apelin on arterial blood pressure
Journal of Neurochemistry, 2004Co-Authors: S El Messari, X Iturrioz, N. De Mota, C. Fassot, Darren M Roesch, Catherine LlorenscortesAbstract:Apelin is a novel neuropeptide involved in the regulation of body fluid homeostasis and cardiovascular functions. It acts through a G protein-coupled receptor, the APJ receptor. We studied the structure-activity relationships of Apelin at the rat Apelin receptor, tagged at its C-terminal end with enhanced green fluorescent protein and stably expressed in CHO cells. We evaluated the potency of N- and C-terminal deleted fragments of K17F to bind with high affinity to the Apelin receptor, and to inhibit cAMP production and to induce Apelin receptor internalization. We first characterized the internalization and trafficking of the rat Apelin receptor. This receptor was internalized via a clathrin-dependent mechanism and our results suggest that receptor trafficking may follow a recycling pathway. We then tried to identify the amino acids of K17F required for Apelin activity. The first five N-terminal and the last two C-terminal amino acids of K17F were not essential for Apelin binding or the inhibition of cAMP production. However, the full-length sequence of K17F was the most potent inducer of Apelin receptor internalization because successive N-terminal amino-acid deletions progressively reduced internalization and the removal of a single amino acid at the C-terminus abolished this process. Finally, the most novel observation of this work is that hypotensive actions of Apelin peptides correlate best with the ability of those ligands to internalize. Thus, Apelin receptor signaling and endocytosis are functionally dissociated, possibly reflecting the existence of several conformational states of this receptor, stabilized by the binding of different Apelin fragments to the Apelin receptor.
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Apelin a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Nadia De Mota, S El Messari, Darren M Roesch, Annabelle Reauxle Goazigo, Nicolas Chartrel, Cynthia Dujardin, C Kordon, Hubert Vaudry, Francoise Moos, Catherine LlorenscortesAbstract:Apelin, a recently isolated neuropeptide that is expressed in the supraoptic and the paraventricular nuclei, acts on specific receptors located on vasopressinergic neurons. The increased phasic pattern of these neurons facilitates sustained antidiuresis during dehydration or lactation. Here, we investigated whether Apelin interacts with arginine vasopressin (AVP) to maintain body fluid homeostasis. We first characterized the predominant molecular forms of endogenous hypothalamic and plasma Apelin as corresponding to Apelin 13 and, to a lesser extent, to Apelin 17. We then demonstrated that, in lactating rats, Apelin was colocalized with AVP in supraoptic nucleus magnocellular neurons and given intracerebroventricularly inhibited the phasic electrical activity of AVP neurons. In lactating mice, intracerebroventricular administration of Apelin 17 reduced plasma AVP levels and increased diuresis. Moreover, water deprivation, which increases systemic AVP release and causes depletion of hypothalamic AVP stores, decreased plasma Apelin concentrations and induced hypothalamic accumulation of the peptide, indicating that AVP and Apelin are conversely regulated to facilitate systemic AVP release and suppress diuresis. Opposite effects of AVP and Apelin are likely to occur at the hypothalamic level through autocrine modulation of the phasic electrical activity of AVP neurons. Altogether, these data demonstrate that Apelin acts as a potent diuretic neuropeptide counteracting AVP actions through inhibition of AVP neuron activity and AVP release. The coexistence of Apelin and AVP in magnocellular neurons, their opposite biological effects, and regulation are likely to play a key role for maintaining body fluid homeostasis.
Daniele Daviaud - One of the best experts on this subject based on the ideXlab platform.
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The intestinal glucose-Apelin cycle controls carbohydrate absorption in mice.
Gastroenterology, 2013Co-Authors: Cedric Dray, Daniele Daviaud, Yassine Sakar, Claire Vinel, Bernard Masri, Luc Garrigues, Estelle Wanecq, Sylvain Galvani, Anne Negre-salvayre, Larry BarakAbstract:BACKGROUND & AIMS: Glucose is absorbed into intestine cells via the sodium glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2); various peptides and hormones control this process. Apelin is a peptide that regulates glucose homeostasis and is produced by proximal digestive cells; we studied whether glucose modulates Apelin secretion by enterocytes and the effects of Apelin on intestinal glucose absorption. METHODS: We characterized glucose-related luminal Apelin secretion in vivo and ex vivo by mass spectroscopy and immunologic techniques. The effects of Apelin on (14)C-labeled glucose transport were determined in jejunal loops and in mice following Apelin gavage. We determined levels of GLUT2 and SGLT-1 proteins and phosphorylation of AMPKα2 by immunoblotting. The net effect of Apelin on intestinal glucose transepithelial transport was determined in mice. RESULTS: Glucose stimulated luminal secretion of the pyroglutaminated Apelin-13 isoform ([Pyr-1]-Apelin-13) in the small intestine of mice. Apelin increased specific glucose flux through the gastric epithelial barrier in jejunal loops and in vivo following oral glucose administration. Conversely, pharmacologic Apelin blockade in the intestine reduced the increased glycemia that occurs following oral glucose administration. Apelin activity was associated with phosphorylation of AMPKα2 and a rapid increase of the GLUT2/SGLT-1 protein ratio in the brush border membrane. CONCLUSIONS: Glucose amplifies its own transport from the intestinal lumen to the bloodstream by increasing luminal Apelin secretion. In the lumen, active Apelin regulates carbohydrate flux through enterocytes by promoting AMPKα2 phosphorylation and modifying the ratio of SGLT-1:GLUT2. The glucose-Apelin cycle might be pharmacologically handled to regulate glucose absorption and assess better control of glucose homeostasis.
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Apelin treatment increases complete Fatty Acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice.
Diabetes, 2012Co-Authors: Camille Attane, Cedric Dray, Daniele Daviaud, Estelle Wanecq, Camille Foussal, Sophie Le Gonidec, Alexandre Benani, Rocío Guzmán-ruiz, Veronic Bezaire, Chloé RancouleAbstract:Both acute and chronic Apelin treatment have been shown to improve insulin sensitivity in mice. However, the effects of Apelin on fatty acid oxidation (FAO) during obesity-related insulin resistance have not yet been addressed. Thus, the aim of the current study was to determine the impact of chronic treatment on lipid use, especially in skeletal muscles. High-fat diet (HFD)-induced obese and insulin-resistant mice treated by an Apelin injection (0.1 μmol/kg/day i.p.) during 4 weeks had decreased fat mass, glycemia, and plasma levels of triglycerides and were protected from hyperinsulinemia compared with HFD PBS-treated mice. Indirect calorimetry experiments showed that Apelin-treated mice had a better use of lipids. The complete FAO, the oxidative capacity, and mitochondrial biogenesis were increased in soleus of Apelin-treated mice. The action of Apelin was AMP-activated protein kinase (AMPK) dependent since all the effects studied were abrogated in HFD Apelin-treated mice with muscle-specific inactive AMPK. Finally, the Apelin-stimulated improvement of oxidative capacity led to decreased levels of acylcarnitines and enhanced insulin-stimulated glucose uptake in soleus. Thus, by promoting complete lipid use in muscle of insulin-resistant mice through mitochondrial biogenesis and tighter matching between FAO and the tricarboxylic acid cycle, Apelin treatment could contribute to insulin sensitivity improvement.
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Apelin and apj regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans
American Journal of Physiology-endocrinology and Metabolism, 2010Co-Authors: Cedric Dray, Daniele Daviaud, Cyrille Debard, Jennifer Jager, Emmanuel Disse, Pascal G P Martin, Camille AttaneAbstract:Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of Apelin and APJ (Apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied Apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, Apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/db mice. In skeletal muscle, Apelin expression was similar in control and HF-fed mice and decreased in db/db mice. APJ expression was decreased in both HF-fed and db/db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal Apelin and APJ expression in AT and muscle between control and diabetic patients. However, Apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased Apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that Apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance.
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Apelin stimulates glucose utilization in normal and obese insulin resistant mice
Cell Metabolism, 2008Co-Authors: Cedric Dray, Claude Knauf, Daniele Daviaud, Jeremie Boucher, Aurelie WagetAbstract:Adipose tissue (AT) secretes several adipokines that influence insulin sensitivity and potentially link obesity to insulin resistance. Apelin, a peptide present in different tissues, is also secreted by adipocytes. Apelin is upregulated in obese and hyperinsulinemic humans and mice. Although a tight relation exists between the regulation of Apelin and insulin, it remains largely unknown whether Apelin affects whole-body glucose utilization. Herein, we show that in chowfed mice, acute intravenous injection of Apelin has a powerful glucose-lowering effect associated with enhanced glucose utilization in skeletal muscle and AT. Through in vivo and in vitro pharmacological and genetic approaches, we demonstrate the involvement of endothelial NO synthase, AMP-activated protein kinase, and Akt in Apelin-stimulated glucose uptake in soleus muscle. Remarkably, in obese and insulin-resistant mice, Apelin restored glucose tolerance and increased glucose utilization. Apelin could thus represent a promising target in the management of insulin resistance.
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effect of hypocaloric diet induced weight loss in obese women on plasma Apelin and adipose tissue expression of Apelin and apj
European Journal of Endocrinology, 2008Co-Authors: Isabelle Castanlaurell, Cedric Dray, Daniele Daviaud, Michaela Vitkova, Michaela Kovacikova, Zuzana Kovacova, J Hejnova, Vladimir Stich, Philippe ValetAbstract:Objective: Apelin is a novel adipokine acting on APJ receptor, regulated by insulin and tumor necrosis factor-a (TNF-a) in adipose tissue (AT). Plasma Apelin levels are increased in obese hyperinsulinemic subjects. The aim was to investigate whether the hypocaloric diet associated with weight loss modifies the elevated plasma Apelin levels and the expression of Apelin and APJ receptor in AT in obese women. Design and methods: Fasting plasma levels of Apelin and TNF-a as well as mRNA levels of Apelin and APJ in AT were measured before and after a 12-week hypocaloric weight-reducing diet in 20 obese women (body mass index (BMI) before diet 32.2G6.4 kg/m 2 ). Twelve healthy women with a BMI of 20.7G 0.6 kg/m 2 served as reference. Results: Plasma levels of Apelin and TNF-a were higher in obese compared with lean controls. The hypocaloric diet resulted in a significant decrease of BMI to 29.8G6.3 kg/m 2 , plasma insulin (8.16G 0.73 to 6.58G0.66 mU/l), Apelin (369G25 pg/ml to 257G12 pg/ml), TNF-a levels (0.66G 0.04 pg/ml to 0.56G0.04 pg/ml), and AT mRNAs of Apelin and APJ. In addition, changes in AT mRNA Apelin were related to changes in AT mRNA APJ levels. Conclusion: The hypocaloric diet associated with weight loss reduces the increased plasma and AT expression of Apelin in obese women. This reduced Apelin expression in AT could contribute to decreased circulating Apelin levels.
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Apelin counteracts vasopressin induced water reabsorption via cross talk between Apelin and vasopressin receptor signaling pathways in the rat collecting duct
Endocrinology, 2014Co-Authors: Annette Huscitharel, Laurence Bodineau, Alain Frugiere, Fanny JoubertAbstract:Apelin receptors (ApelinRs) are expressed along an increasing cortico-medullary gradient in collecting ducts (CDs). We showed here that iv injection of Apelin 17 (K17F) in lactating rats characterized by increases in both synthesis and release of arginine vasopressin (AVP) increased diuresis concomitantly with a significant decrease in urine osmolality and no change in Na(+) and K(+) excretion. Under these conditions, we also observed a significant decrease in apical aquaporin-2 immunolabeling in CD, with a cortico-medullary gradient, suggesting that K17F-induced diuresis could be linked to a direct action of Apelin on CD. We then examined the potential cross talk between V1a AVP receptor (V1a-R), V2 AVP receptor (V2-R) and ApelinR signaling pathways in outer medullary CD (OMCD) and inner medullary CD microdissected rat CD. In OMCD, expressing the 3 receptors, K17F inhibited cAMP production and Ca(2+) influx induced by 1-desamino-8-D-arginine vasopressin a V2-R agonist. Similar effects were observed in inner medullary CD expressing only V2-R and ApelinR. In contrast, in OMCD, K17F increased by 51% the Ca(2+) influx induced by the stimulation of V1a-R by AVP in the presence of the V2-R antagonist SR121463B, possibly enhancing the physiological antagonist effect of V1a-R on V2-R. Thus, the diuretic effect of Apelin is not only due to a central effect by inhibiting AVP release in the blood circulation as previously shown but also to a direct action of Apelin on CD, by counteracting the antidiuretic effect of AVP occurring via V2-R.
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Apelin counteracts vasopressin induced water reabsorption via cross talk between Apelin and vasopressin receptor signaling pathways in the rat collecting duct
Endocrinology, 2014Co-Authors: Annette Huscitharel, Laurence Bodineau, Alain Frugiere, Fanny JoubertAbstract:Apelin receptors (ApelinRs) are expressed along an increasing cortico-medullary gradient in collecting ducts (CDs). We showed here that iv injection of Apelin 17 (K17F) in lactating rats characterized by increases in both synthesis and release of arginine vasopressin (AVP) increased diuresis concomitantly with a significant decrease in urine osmolality and no change in Na+ and K+ excretion. Under these conditions, we also observed a significant decrease in apical aquaporin-2 immunolabeling in CD, with a cortico-medullary gradient, suggesting that K17F-induced diuresis could be linked to a direct action of Apelin on CD. We then examined the potential cross talk between V1a AVP receptor (V1a-R), V2 AVP receptor (V2-R) and ApelinR signaling pathways in outer medullary CD (OMCD) and inner medullary CD microdissected rat CD. In OMCD, expressing the 3 receptors, K17F inhibited cAMP production and Ca2+ influx induced by 1-desamino-8-D-arginine vasopressin a V2-R agonist. Similar effects were observed in inner me...