Llorens-Cortes

Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions

Principal Investigator: Catherine LLORENS-CORTES, DRCE Inserm

The Brain Renin-Angiotensin System (RAS)

Over the last few years, we have obtained a number of important results, including the demonstration that aminopeptidase A (APA) and aminopeptidase N (APN), two zinc ectoenzymes, are involved in the conversion of angiotensin II (AngII) into AngIII and in that of AngIII to AngIV, respectively,in the brain. Then, in collaboration with the team of B.P. Roques, we designed the first specific and selective APA inhibitor, EC33 (Figure 1). Then, by blocking in vivo APA and APN with specific and selective inhibitors, we were able to show, for the first time, that one of the main effector peptides of the brain RAS was AngIII, and not AngII, as established in the periphery. This work showed that AngIII in the brain increases the activity of vasopressin (AVP) neurons and exerts a tonic stimulatory effect on the control of blood pressure (BP) in hypertensive rats. Thus, the central injection of EC33, by blocking the formation of brain AngIII, normalizes BP in hypertensive rats. These findings strongly suggest that brain APA is a potential therapeutic target for the treatment of arterial hypertension (HTA), justifying efforts to develop potent and selective APA inhibitors able to enter the brain after oral administration, as central-acting antihypertensive agents. For this purpose, in coll. with the team of B.P. Roques, a prodrug of EC33, RB150 was developed. We then showed that RB150 is able after administration by oral route, to cross the intestinal, hepatic and blood brain barriers, to block the activity of the brain RAS and to normalize BP i) in hypertensive DOCA-salt rats which are characterized by low plasma renin activity and a resistance to systemic RAS blockers treatment and ii) in spontaneously hypertensive rats (SHR) which are considered to be a relevant model of essential hypertension sensitive to systemic RAS blockers. The anti-hypertensive effect of RB150 is due in part i) to a decrease in systemic AVP release, increasing diuresis, reducing extracellular volume, ii) to a decrease in sympathetic tone, consequently reducing vascular resistances and iii) to an improvement of the baroreflex function (Figure 2). For a potential clinical use of RB150, we established that the biochemical and enzymatic properties of APA in the human brain, especially its sensitivity to EC33, together with its brain distribution are identical to those found in the rodent brain. The collaboration with Quantum Genomics Company has allowed the evaluation of the bioavailability, genotoxicity and toxicity of RB150 in animals. Finally, RB150/QGC001 has received the agreement from the French National Agency of Medecine and Health Products Safety (AFSSAPS now ANSM) on April 13th 2012, for the first clinical trial, Phase I in healthy volunteers. The results of the Phase I a Study of RB150/QGC001 show that single oral administration up to 1,250 mg in healthy volunteers was safe and well-tolerated. The Phase Ib Study on the effects of multiple oral doses of RB150 in human volunteers is now achieved and the analysis of the datas are in progress. The clinical efficacy of RB150/QGC001 in hypertensive patients will be evaluated in 2014-2015 in the Clinical Investigation Center (CIC) of European Georges Pompidou Hospital (HEGP) directed by Pr M Azizi and received a financial support from ANR RPIB.
The clinical study was achieved at the end of 2016 and the analysis of the datas are in progress. For information see the press release. In parallel, we performed studies in heart failure rats post-myocardial infarction (Cardiovasc. Res., 2013) in collaboration with Prof. F. Leenen (Heart Institute, Ottawa), which demonstrate another possible application for RB150 in the treatment of heart failure by normalizing sympathetic hyperactivity, decreasing hypertrophy and improving cardiac function.

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CortesCLC-Fig_1_new-PartA
CortesCLC-Fig_1_new-PartB

3D model of aminopeptidase A (APA) in which the specific and selective APA inhibitor EC33 was docked.

Llorens-Fig3

Metabolic pathways of AngII and AngIII in the brain involving the zinc-metalloprotease APA.

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The Apelinergic System

Our efforts to clone an AngIII receptor led to isolate in the rat brain, an orphan receptor which was subsequently shown to be the receptor of a new peptide, apelin. We demonstrated that apelin and its receptor were expressed together with AVP and oxytocin in magnocellular hypothalamic neurons. We showed that the icv injection of apelin in lactating rats decreased the phasic electrical activity of AVP neurons and the secretion of AVP into the bloodstream, increasing aqueous diuresis. Apelin has also a diuretic effect via a direct renal action by increasing renal microcirculation and by counteracting the antidiuretic effect of AVP at the tubular level. Apelin is thus a natural inhibitor of the anti-diuretic effect of AVP. After water deprivation, magnocellular AVP neurons are strongly activated and AVP is released into the blood circulation faster than it is synthesised, resulting in a depletion of AVP stores in the soma, whereas apelin accumulates within neurons rather than being released (Figure 3). The opposite regulation of AVP and apelin after dehydration allows to optimize systemic AVP release and to avoid additional water loss at the kidney level.
By contrast, under water loading, neurons are inhibited, which stops AVP release and results in the accumulation of AVP in the soma. Apelin release in the bloodstream is rapidly increased, faster than its synthesis, resulting in a depletion of neuronal apelin content (Figure 3). Thus, both neuronal and plasma apelin levels are regulated by osmotic stimuli in an opposite direction to AVP. This shows that apelin like AVP plays a crucial role in the maintenance of body fluid homeostasis. Furthermore, we also observed such opposite regulation of plasma apelin and AVP levels in human volunteers after salt loading and apelin and AVP secretions in humans are significantly altered in various water metabolism disorders including hyponatremia and polyuria-polydipsia syndrome.
Apelin and its receptor are also present in the cardiovascular system and the systemic injection of apelin decreases BP, improves cardiac contractility and reduces cardiac loading. Apelin may therefore play a crucial role in maintaining water and electrolyte balance and cardiovascular function. We also showed that apelin and its receptor colocalize with POMC in arcuate nucleus neurons and apelin increases alpha-MSH release, supporting the hypothesis that central apelin is involved in regulating body weight and feeding behavior. Since patients with high BP are often overweight or even obese, apelin could represent a common endogenous substrate for both pathologies.
The half-life of apelin in the blood circulation being around 1 min, in order to identify non peptidic apelin receptor agonists we first used an original FRET-based assay to screen a library of fluorescent compounds on the human EGFP-tagged apelin receptor in coll. with the laboratory of Pr M. Hibert and the team of Dr Dominique Bonnet. We isolated several hits, the most potent being E339-3D6, which displayed an affinity of 90 nM, behaved as a partial agonist with regard to cAMP production and as a full agonist with regard to apelin receptor internalization. However, this compound does not reach the clinical standard requirements, because of its high molecular weight, the presence of a fluorophore lissamine and a relatively weak selectivity.

In parallel to the optimization of E339-3D6, we developped metabolically stable apelin-17 (K17F) analogs. We generated P92 by classic chemical substitutions and LIT01-196 by original addition of a fluorocarbon chain to the N terminus of K17F. Both analogs were much more stable in plasma (half-life >24 h for LIT01-196) than K17F (4.6 min). Analogs displayed a subnanomolar affinity for the apelin receptor and behaved as full agonists with regard to cAMP production, ERK phosphorylation, and apelin receptor internalization. Ex vivo, these compounds induced vasorelaxation of rat aorta and glomerular arterioles, respectively, precontracted with norepinephrine and angiotensin II, and increased cardiac contractility. In vivo, after intracerebroventricular administration in water-deprived mice, P92 and LIT01-196 were 6 and 160 times, respectively, more efficient at inhibiting systemic vasopressin release than K17F. Administered intravenously (nmol/kg range) in normotensive rats, these analogs potently increased urine output and induced a profound and sustained decrease in arterial blood pressure. In conclusion, these new compounds, which favor diuresis and improve cardiac contractility while reducing vascular resistances, represent promising candidates for the treatment of heart failure and water retention/hyponatremic disorders.

CLC-fig3New

Yin–Yang type function of dual vasopressin (VP; purple) and apelin (Ap; green) neurons

Scientific Projections

Currently treatments against HTA act on the vessels, heart or elimination of water and salt in the urine and two or three drugs are used to normalize BP. The benefit of treatment with RB150/QGC001 is that with a single treatment, by blocking the brain RAS, we will normalize BP by regulating the activity at the level of the kidney by reducing the secretion of vasopressin (diuretic effect), of the vessels by decreasing the sympathetic tone (reduction of vascular resistances) and at the level of the heart, by suppressing the inhibition exerted by brain angiotensin on the baroreflex. All of this research could lead to the development of a new centrally-acting antihypertensive agent. Another possible application of RB150 is its use to prevent the development of heart failure after myocardial infarction.
Our work and studies of other laboratories have shown the beneficial role of apelin in controlling body fluid homeostasis and cardiovascular functions. Thus metabolically stable apelin analogs which favor diuresis and improve cardiac contractility while reducing vascular resistances, represent promising candidates for the treatment of heart failure and water retention/ hyponatremic disorders.

Prize

The 2012 Daniele Hermann Prize (Fondation Recherche Cardio-Vasculaire - Institut de France) has been awarded to Dr Catherine Llorens-Cortes.

Laureate of the 2014 Prix Galien France (prize of pharmaceutical research, research section).

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Fondation Recherche Cardio-Vasculaire

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Selected Publications 2004-2017

- Valencia, C., Dujet, C., Margathe, J.-F., Iturrioz, X., Roux, T., Trinquet, E., Villa, P., Hibert, M., Dupuis, E., Llorens-Cortes, C. & Bonnet, D. (2017), Time-Resolved FRET Cell-Based Binding Assay For Apelin Receptor. ChemMedChem. 

- Couvineau, P., de Almeida, H., Maigret, B., Llorens-Cortes, C. & Iturrioz, X. (2017), Involvement of arginine 878 together with Ca2+ in mouse aminopeptidase A substrate specificity for N-terminal acidic amino-acid residues. PLoS ONE 12, e0184237.

- Flahault, A., Couvineau, P., Alvear-Perez, R., Iturrioz, X. & Llorens-Cortes, C. (2017), Role of the Vasopressin/Apelin Balance and Potential Use of Metabolically Stable Apelin Analogs in Water Metabolism Disorders. Front Endocrinol (Lausanne) 8, 120.

- McKinnie, S.M.K., Wang, W., Fischer, C., McDonald, T., Kalin, K.R., Iturrioz, X., Llorens-Cortes, C., Oudit, G.Y. & Vederas, J.C. (2017), Synthetic Modification within the “RPRL” Region of Apelin Peptides: Impact on Cardiovascular Activity and Stability to Neprilysin and Plasma Degradation. J. Med. Chem. 60, 6408–6427.

- Gerbier, R., Alvear-Perez, R., Margathe, J.-F., Flahault, A., Couvineau, P., Gao, J., De Mota, N., Dabire, H., Li, B., Ceraudo, E., Hus-Citharel, A., Esteoulle, L., Bisoo, C., Hibert, M., Berdeaux, A., Iturrioz, X., Bonnet, D. & Llorens-Cortes, C. (2017), Development of original metabolically-stable apelin-17 analogs with diuretic and cardiovascular effects. FASEB J. 31, 687-700.

- Barrow-McGee, R., Kishi, N., Joffre, C., Ménard, L., Hervieu, A., Bakhouche, B.A., Noval, A.J., Mai, A., Guzmán, C., Robbez-Masson, L., Iturrioz, X., Hulit, J., Brennan, C.H., Hart, I.R., Parker, P.J., Ivaska, J. & Kermorgant, S. (2016), Corrigendum: Beta 1-integrin-c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes. Nat Commun 7, 12392.

- Wang W., Mckinnie SM., Farhan M., Paul M., Mcdonald T., Mclean B., Llorens-Cortes C., Hazra S., Murray AG., Vederas JC. & Oudit GY. (2016), Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System. Hypertension. 68(2), 365-77.

- Urwyler, S.A., Timper, K., Fenske, W., de Mota, N., Blanchard, A., Kühn, F., Frech, N., Arici, B., Rutishauser, J., Kopp, P., Stettler, C., Müller, B., Katan, M., Llorens-Cortes, C. & Christ-Crain, M. (2016), Plasma Apelin concentrations in Patients with Polyuria-Polydipsia Syndrome. J. Clin. Endocrinol. Metab. 101(5):1917-23.

- Margathe, J.-F., Iturrioz, X., Regenass, P., Karpenko, I.A., Humbert, N., de Rocquigny, H., Hibert, M., Llorens-Cortes, C. & Bonnet, D. (2016), Convenient Access to Fluorescent Probes by Chemoselective Acylation of Hydrazinopeptides: Application to the Synthesis of the First Far-Red Ligand for Apelin Receptor Imaging. Chemistry, 22(4):1399-405.

- Friis, K.P., Iturrioz, X., Thomsen, J., Alvear-Perez, R., Bahrami, S., Llorens-Cortes, C. & Pedersen, F.S. (2015), Directed molecular evolution of an engineered gammaretroviral envelope protein with dual receptor use shows stable maintenance of both receptor specificities. J. Virol. 25;90(3):1647-56.

- Gerbier R., Leroux V., Couvineau P., Alvear-Perez R., Maigret B., Llorens-Cortes C. & Iturrioz X. (2015), New structural insights into the apelin receptor: identification of key residues for apelin binding. FASEB J. 29, 314–322. 

- Llorens-Cortès C. (2014), Orally active aminopeptidase A inhibitors reduce blood pressure: a new strategy for treating hypertension. Biol Aujourdhui 208, 217–224. 

- Margathe, J.-F., Iturrioz, X., Alvear-Perez, R., Marsol, C., Riché, S., Chabane, H., Tounsi, N., Kuhry, M., Heissler, D., Hibert, M., Llorens-Cortes C & Bonnet D (2014), Structure–Activity Relationship Studies toward the Discovery of Selective Apelin Receptor Agonists. J. Med. Chem. 57, 2908–2919.

- Gerbier, R., Leroux, V., Couvineau, P., Alvear-Perez, R., Maigret, B., Llorens-Cortes, C. & Iturrioz, X. (2014), New structural insights into the apelin receptor: identification of key residues for apelin binding. FASEB J.

- Balavoine, F., Azizi, M., Bergerot, D., De Mota, N., Patouret, R., Roques, B.P. & Llorens-Cortes, C. (2014), Randomised, double-blind, placebo-controlled, dose-escalating phase I study of QGC001, a centrally acting aminopeptidase a inhibitor prodrug. Clin Pharmacokinet, 53, 385–395.

- Ceraudo, E., Galanth, C., Carpentier, E., Banegas-Font, I., Schonegge, A.-M., Alvear-Perez, R., Iturrioz, X., Bouvier, M. & Llorens-Cortes, C. (2014), Biased signaling favoring Gi over β-arrestin promoted by an apelin fragment lacking the C-terminal phenylalanine. J. Biol. Chem, 289(35):24599-610.

- Hus-Citharel A., Bodineau L., Frugière A., Joubert F., Bouby N. & Llorens-Cortes C. (2014), Apelin counteracts vasopressin-induced water reabsorption via crosstalk between apelin and vasopressin receptor signaling pathways in the rat collecting duct. Endocrinology, en20141257.

- Sauvant J., Delpech J.-C., Palin K., De Mota N., Dudit J., Aubert A., Orcel H., Roux P., Layé S., Moos F., Llorens-Cortes C. & Nadjar A. (2014), Mechanisms Involved in Dual Vasopressin/Apelin Neuron Dysfunction during Aging. PLoS ONE 9, e87421.

- Gao J., Marc Y., Iturrioz X., Leroux V., Balavoine, F. & Llorens-Cortes C. (2014), A new strategy for treating hypertension by blocking the activity of the brain renin-angiotensin system with aminopeptidase A inhibitors. Clin. Sci. 127, 135–148.

- Margathe J.-F., Iturrioz X., Alvear-Perez R., Marsol C., Riché S., Chabane H., Tounsi N., Kuhry M., Heissler D., Hibert M., Llorens-Cortes C. &  Bonnet D. (2014), Structure–Activity Relationship Studies toward the Discovery of Selective Apelin Receptor Agonists, Journal of medicinal chemistry, 57 (7), pp 2908–2919.

- Blanchard A., Steichen O., De Mota N., Curis E., Gauci C., Frank M., Wuerzner G., Kamenicky P., Passeron A., Azizi M. & Llorens-Cortes C. (2013), An abnormal apelin/vasopressin balance may contribute to water retention in patients with the syndrome of inappropriate antidiuretic hormone (SIADH) and heart failure. J. Clin. Endocrinol. Metab. May;98(5):2084-9.

- Huang B.S., Ahmad M., White R.A., Marc Y., Llorens-Cortes C. & Leenen F.H.H. (2013), Inhibition of brain angiotensin III attenuates sympathetic hyperactivity and cardiac dysfunction in rats post-myocardial infarction. Cardiovasc. Res. 97, 424-431.

- Galanth C., Hus-Citharel A., Li B. & Llorens-Cortes C. (2012), Apelin in the control of body fluid homeostasis and cardiovascular functions. Curr Pharm Des, 18(6):789-98.

- Marc Y., Ji G., Balavoine F., Michaud A., Roques B. & Llorens-Cortes C. (2012), Central antihypertensive effects of orally active aminopeptidase a inhibitors in spontaneously hypertensive rats. Hypertension, 60(2):411-8.

- Iturrioz X., O-Wang J., Cooper M.D. & Llorens-Cortes C. (2012), Glutamyl Aminopeptidase. In Barret A., Rawlings N.D. and J. Woessner (eds), Handbook of proteolytic enzymes (3rd edition), Academic press: Oxford, pp 410-414.

- Llorens-Cortes C. & Moos F. (2012), Apelin and vasopressin: two work better than one. J Neuroendocrinol, 24(7):1085-6.

- Bodineau L., Taveau C., Le Quan Sang H-H., Osterstock G., Queguiner I., Moos F., Frugiere A. & Llorens-Cortes C. (2011), Data supporting a new physiological role for brain apelin in the regulation of endocrine oxytocin neurons in lactating rats. Endocrinology, 152(9):3492-503.

- Duparc T., Colom A., Cani P.D., Massaly N., Rastrelli S., Le Gonidec S., Mouledous L., Frances B., Llorens Cortes C., Pospisilik J.A., Penninger J.M., Delzenne N.M., Valet P., Castan-Laurell I. & Knauf C. (2011), Central Apelin controls Glucose Homeostasis via a NO dependent pathway: Mechanism Impaired in High-Fat Diet. Antioxid Redox Signal, 15(6):1477-96.

- Reaux-Le Goazigo A., Bodineau L., De Mota N., Jeandel L., Chartrel N., Knauf C., Raad C, Valet P. & Llorens-Cortes C. (2011), Apelin and the proopiomelanocortin system: a new regulatory pathway of hypothalamic α-MSH release. Am J Physiol Endocrinol Metab, 301(5):E955-66.

- Feng DD., Yang SK., Loudes C., Simon A., Al-Sarraf T., Culler M., Alvear-Perez R., Llorens-Cortes C., Chen C., Epelbaum J. & Gardette R. (2011), Ghrelin and obestatinmodulategrowth hormone-releasing hormone release and synaptic inputs onto growth hormone-releasing hormone neurons. Eur. J. Neurosci., Sep;34(5):732-44.

- Marc Y. & Llorens-Cortes C. (2011), The role of the brain renin-angiotensin system in hypertension: implications for new treatment. Prog Neurobiol, 95(2):89-103.

- Chartrel N., Alonzeau J., Alexandre D., Jeandel L., Alvear R., Vaudry H., Leprince J., Boutin J., Anouar Y., Llorens-Cortes C. (2011), The RFamide neuropeptide 26RFa and its role in the control of neuroendocrine functions. Front Neuroendocrinol, 32(4):387-97.

- Hus-Citharel A., Bouby N., Iturrioz X. & Llorens-Cortes C. (2010), Multiple crosstalk between angiotensin ii, bradykinin and insulin signaling in the rat cortical thick ascending limb. Endocrinology, 151(7):3181-94.

- Bodineau L., Hus-Citharel A. &Llorens-Cortes C. (2010), Contribution of apelin to water balance, blood glucose control, and cardiovascularfunctions. Ann. Endocrinol. (Paris), Sep;71(4):249-56.

- Iturrioz X., Gerbier R., Leroux V., Alvear-Perez R., Maigret B. & Llorens-Cortes C. (2010), By interacting with the C-terminal PHE of apelin, PHE 255 and TRP 259 in helix VI of the apelin receptor are critical for internalization. J Biol Chem., 285, 32627-32637.

- Claperon C., Banegas-Font I., Iturrioz X., Rozenfeld R., Maigret B. & Llorens-Cortes C. (2009), Identification of threonine 348 as a residue involved in aminopeptidase A substrate specificity. J Biol Chem, 284(16): 10618-26.

- Iturrioz X., Reaux-Le Goazigo A., Moos F. &Llorens-Cortes C., (2009), Apelin and Vasopressin, in M Bader (ed.), Cardiovascular Hormone Systems. From Molecular Mechanisms to Novel Therapeutics, Wiley-VchVerlag GMBH & CO. KGAA, Weinheim, pp. 193-208.

- Bodineau L., Hus-Citharel A. &Llorens-Cortes C. (2009), Participation de l'apéline au maintien de l'équilibre hydrique et des fonctions cardiovasculaires, ActualitesNephrologiques.vol. 50, pp. 127-138.

- Iturrioz X., Alvear-Perez R., De Mota N., Franchet C., Guillier F., Leroux V., Dabire H., Le Jouan M., Chabane H., Gerbier R., Bonnet D., Berdeaux A., Maigret B., Galzi Jl., Hibert M. & Llorens-Cortes C. (2009), Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist. FASEB J., 24(5):1506-17.

- Llorens-Cortes C. & Moos F. (2008), Opposite potentiality of hypothalamiccoexpressed neuropeptides, apelin and vasopressin in maintaining body-fluidhomeostasis. Prog. BrainRes., 170:559-70.

- Claperon C., Rozenfeld R., Iturrioz X., Inguimbert N., Okada M., Roques B., Maigret B. &Llorens-Cortes C. (2008), Asp218 participateswith Asp213 to bind a Ca2+ atominto the S1 subsite of aminopeptidase A: a keyelement for substratespecificity. Biochem. J., 15;416(1):37-46.

- Hus-Citharel A., Bouby N., Frugiere A., Bodineau L., Gasc JM. &Llorens-Cortes C. (2008), Effect of apelin on glomerularhemodynamicfunction in the rat kidney. Kidney Int., 74(4): 486-94.

- De Mota N., Iturrioz X., Claperon C., Bodineau L., Fassot C., Roques BP., Palkovits M. &Llorens-Cortes C. (2008), Humanbrainaminopeptidase A: biochemicalproperties and distribution in brainnuclei. J. Neurochem., 106(1): 416-28.

- Reaux-Le Goazigo A., Iturrioz X. &Llorens-Cortes C. (2009), Apelin and receptor, in Squire Lr (ed.), Encyclopedia Of Neuroscience, Academic Press, Oxford, pp. 509-516. 

- Bodineau L., Frugiere A., Marc Y., Inguimbert N., Fassot C., Roques B. & Llorens-Cortes C. (2008), Orally active aminopeptidase A inhibitors reduce blood pressure by inhibiting the brain-renin-angiotensin system: a new strategy for treating hypertension. Hypertension, 51(5): 1318-25.

- Azizi M., Iturrioz X., Blanchard A., Peyrard S., De Mota N., Chartrel N., Vaudry H., Corvol P. & Llorens-Cortes C. (2008), Reciprocal regulation of plasma apelin and vasopressin by osmotic stimuli. J Am Soc Nephrol, 19(5): 1015-24.

- Llorens-Cortes C. &Kordon C. (2008), Jacques Benoit lecture: the neuroendocrine view of the angiotensin and apelinsystems. J. Neuroendocrinol., 20(3):279-89.

- Bodineau L., Frugière A., Marc Y., Claperon C. &Llorens-Cortes C. (2008) Aminopeptidase A inhibitors as centrally acting antihypertensive agents. Heart Fail. Rev. 13(3):311-9. Review.

- Iturrioz X., El Messari S., De Mota N., Fassot C., Alvear-Perez R., Maigret B. &Llorens-Cortes C. (2007), Functional dissociation betweenapelinreceptorsignaling and endocytosis: implications for the effects of apelin on arterialblood pressure. Arch. Mal. CoeurVaiss., 100(8):704-8.

- Chartrel N., Alvear-Perez R., Leprince J., Iturrioz X., Reaux-Le Goazigo A., Audinot V., Chomarat P., Coge F., Nosjean O., Rodriguez M., Galizzi Jp, Boutin Ja., Vaudry H. & Llorens-Cortes C. (2007), Comment on "obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science, 315(5813): 766.

- Reaux-Le Goazigo A., Alvear-Perez R., Zizzari P., Epelbaum J., Bluet-Pajot MT. & Llorens-Cortes C. (2007), Cellular localization of apelin and itsreceptor in the anteriorpituitary: evidence for a direct stimulatory action of apelin on ACTH release. Am. J. Physiol. Endocrinol. Metab., 292(1): E7-15.

- Carreira M.C., Camiña J.P., Díaz-Rodríguez E., Alvear-Perez R., Llorens-Cortes C. & Casanueva FF. (2006), Adenosinedoes not bind to the growth hormone secretagoguereceptor type-1a (GHS-R1a). J. Endocrinol., 191(1):147-57.

- Hus-Citharel A., Iturrioz X., Corvol P., Marchetti J. & Llorens-Cortes C. (2006), Tyrosine kinase and mitogen-activatedprotein kinase/extracellularlyregulated kinase differentiallyregulateintracellular calcium concentration responses to angiotensin II/III and bradykinin in rat cortical thickascendinglimb. Endocrinology. 147(1):451-63.

- Wilson WL., Roques BP., Llorens-Cortes C., Speth RC., Harding JW. & Wright JW. (2005), Roles of brainangiotensins II and III in thirst and sodium appetite. BrainRes. 1060(1-2):108-17.

- Llorens-Cortès C. & Beaudet A. (2005), Apelin, a neuropeptide thatcounteractsvasopressinsecretion]. Med. Sci. (Paris). 21(8-9):741-6. Review.

- Reaux-Le Goazigo A., Iturrioz X., Fassot C., Claperon C., Roques BP. &Llorens-Cortes C. (2005), Role of angiotensin III in hypertension. CurrHypertensRep. 7(2):128-34. Review.

- Inguimbert N., Coric P., Dhotel H., Bonnard E., Llorens-Cortes C., Mota N., Fournié-Zaluski MC. & Roques BP. (2005), Synthesis and in vitro activities of new non-peptidic APA inhibitors. J PeptRes. 65(2):175-88.

- El Messari S., Iturrioz X., Fassot C., De Mota N., Roesch D. &Llorens-Cortes C. (2004), Functional dissociation of apelinreceptorsignaling and endocytosis: implications for the effects of apelin on arterialblood pressure. J Neurochem. 90(6):1290-301.

- Rozenfeld R., Muller L., El Messari S. &Llorens-Cortes C. (2004), The C-terminal domain of aminopeptidase A is an intramolecularchaperonerequired for the correct folding, cell surface expression and activity of thismonozincaminopeptidase. J.Biol.Chem., 279(41):43285-95.

- Fournie-Zaluski M.-C., Fassot C., Valentin B., Djordjijevic D., Reaux-Le Gaozigo A., Corvol P., Roques B.P & Llorens-Cortes C. (2004), Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: a potential treatment of salt-dependent hypertension. Proc Natl Acad Sci, USA, 101(20): 7775-80.

- De Mota N., Reaux-Le Goazigo A., El Messari S., Chartrel N., Roesch D., Dujardin C., Kordon C., Vaudry H., Moos F. & Llorens-Cortes C. (2004), Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc Natl Acad Sci, USA, 101(28): 10464-9.

- Camiña JP., Carreira MC., El Messari S., Llorens-Cortes C., Smith RG. & Casanueva FF. (2004) Desensitization and endocytosismechanisms of ghrelin-activatedgrowth hormone secretagoguereceptor 1a. Endocrinology, 145(2):930-40.

- Reaux-Le Goazigo A., Morinville A., Burlet A., Llorens-Cortes C. & Beaudet A. (2004), Dehydration-induced cross-regulation of apelin and vasopressinimmunoreactivitylevels in magnocellularhypothalamicneurons. Endocrinology, 145(9):4392-400.

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Invitations and Seminars

2004: Gordon Research Conference On Angiotensin, Ventura – USA.
2005: American Physiological Society Conference – Steamboat Springs, Colorado, USA.
2006: 6th International Congress of Neuroendocrinology. J. Benoit Lecture. Pittsburgh, USA.
2007: Lilly 2007, Genesis Investigator Meeting, Paris, France.
VIIth World Congress on Neurohypophysial Hormones, Regensburg, Germany.
2008: Seminar of the Chair of Experimental Medicine organized by Pr P. Corvol & C. Llorens-Cortes entitled “New Data on G-Protein Coupled Receptors”, Collège de France, Paris, France.
2009: Joint Meeting Peptide Receptor/Kinin 2009, Quebec, Canada.
XVIIIth Scientific Meeting of the Inter-American Society of Hypertension and Renin Angiontensin Aldosterone System Satellite Belo Horizonte, Brazil.
2010: The 7th International Congress of Neuroendocrinology Rouen, France: member of the International Program Organizing Committee.
- 18th International Symposium on Regulatory Peptides, Belfast, Northern Ireland, UK.
Cardiovascular Conference, Puerto Morelos, Mexico.
2011: First International Symposium of Neuroendocrinology, Hotel Campina Verde-São Pedro, Brésil.
- 36th European Symposium on Hormones and Cell Regulation, Mont Sainte Odile, France
2012: Gordon Research Conference on Angiotensin, Ventura, USA.
- Focus Association for Clinical Biochemistry National Meeting, Liverpool, UK.
- Kinin 2012, Third International Symposium on "Vasoactive and Inflammatory Mediators, Pathophysiology and treatment of metabolic, ischemic and proliferative disorders”, Paris, France.
2013: 23rd European Meeting On Hypertension And Cardiovascular Protection - Milan, Italie (June 14-17)
- 39ème Colloque de la Société de Neuroendocrinologie - Fès, Maroc (25-27 septembre)
- Symposium “40 years of the microdissection of the brain” en l’honneur du Pr. M. Palkovits, Académie des Sciences Hongroise - Budapest, Hongrie (November 20)
- 33ème Journées de l’Hypertension Artérielle - 7th International Meeting of the French Society of Hypertension - Palais de Congrès, Paris, France (December 19-20)
- 2nd Annual Meeting of the GDR RCPG-Physio-Med - Illkirch, France, (October 14-16)
2014: Joint Meeting of the Federation of European Physiological Societies (FEPS) and the Hungarian Physiological Society - Budapest, Hongary (August 27-30)
- Joint Meeting ESH-ISH - Hypertension, Athenes, Grèce (June 13-16)
- 8th Annual Meeting of the European-Council-for-Cardiovascular-Research (ECCR) - Lake de Garde, Italie (October 24-26)
2015: 22ème Réunion Scientifique Annuelle de la Société Québécoise d'Hypertention Artérielle - Montréal, Canada (January 20-23) - Conférence de la Présidente
- Xth International Symposium on Vasoactive Peptides - Minas Gerais, Brésil (October 29-31).
- Plenary lecture given by Catherine Llorens-Cortes at the 5ème Annual Conference of the LabEx LERMIT on december 11, Ecole Normale Supérieure de Cachan.
2016: 26th European Meeting on Hypertension and Cardiovascular Protection. Palais des Congrès, Paris, France (June 10-13)
- REGPEP 2016 International Regulatory Peptide Meeting, Rouen, France (July11-15)
- 17th Congress of the European Neuroendocrine Association Milan, Italy (19-22 October)
- American Heart Association's Annual Scientific Sessions New Orleans, USA (November 12-16)

People

Group leader:
Llorens-Cortes Catherine, DRCE INSERM

Senior Researchers:
Iturrioz Xavier, CR1 INSERM
Maigret Bernard, DRCE CNRS
Marc Yannick, CR Quantum Genomics
Compere Delphine, CR Quantum Genomics
Keck Mathilde, CR Quantum Genomics

Postdoctoral fellows, PhD Students & Master student:
De Almeida-Silva Hugo, CDD INSERM, Post-doc
Boitard Solene, CDD Quantum Genomics, Post-doc
Couvineau Pierre, PhD student
Hmazzou Reda, PhD student
Flahault Adrien, PhD student
Barakat Fouad, Master student

Technical staff:
Alvear-Perez Rodrigo, IE2 INSERM
De Mota-Picco Nadia, TCS CDF
Bisoo Cynthia, IE CDD INSERM