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Thèse Et Mémoire Université de Montréal Les effets cardioprotecteurs de peptides dérivés des sécrétagogues de l’hormone de croissance dans le modèle d’ischémie-reperfusion du myocarde murin par David Nghi-Nhien Huynh Faculté de pharmacie Thèse présentée à la Faculté des études supérieures et postdoctorales en vue de l’obtention du grade de Philosophiae Doctor (Ph.D) en sciences pharmaceutiques option pharmacologie Août, 2018 © David Nghi-Nhien Huynh, 2018 Université de Montréal Faculté des études supérieures et postdoctorales Cette thèse intitulée : Les effets cardioprotecteurs de peptides dérivés des sécrétagogues de l’hormone de croissance dans le modèle d’ischémie-reperfusion du myocarde murin Présentée par : David Nghi-Nhien Huynh a été évaluée par un jury composé des personnes suivantes : Denis deBlois, président-rapporteur Sylvie Marleau, directeur de recherche Huy Ong, co-directeur Guy Rousseau, membre du jury David St-Pierre, examinateur externe i Résumé Les peptides sécrétagogues de l’hormone de croissance (GHRP) sont des peptides synthétiques qui stimulent la sécrétion de l’hormone de croissance (HC) après la liaison avec le récepteur de la ghréline (antérieurement appelé le récepteur 1a des sécrétagogues de l’hormone de croissance, GHS-R1a). La ghréline désacylée (UAG) est la forme prédominante de la ghréline en circulation, mais l’UAG ne lie pas le récepteur de la ghréline et ne stimule pas la sécrétion d’hormone de croissance. Des études ont montré que les GHRPs et l’UAG possèdent des effets cardioprotecteurs indépendants de la sécrétion de l’hormone de croissance. L’équipe de Ong a identifié le récepteur CD36, exprimé entre autres par les cardiomyocytes, les macrophages et les adipocytes, comme étant un deuxième site de liaison pour les GHRPs, tandis que le récepteur de l’UAG reste encore inconnu à ce jour. L’objectif général de cette thèse était d’évaluer les effets cardioprotecteurs d’une nouvelle classe d’analogues des GHRPs, les azapeptides, qui présentent une plus grande sélectivité envers le récepteur CD36 par comparaison à celui de la ghréline, et les effets cardioprotecteurs d’un fragment peptidique bioactif de l’UAG, l’UAG6-13, dans la pathologie de la maladie cardiaque ischémique. Le modèle d’ischémie/reperfusion du myocarde (I/RM) a été produit par une ligature chirurgicale de l’artère coronaire antérieure descendante gauche pendant 30 min pour induire une ischémie, suivie d’une reperfusion de 6 ou 48 h chez des souris mâles C57BL/6. Les souris ont été prétraitées dans la première étude avec l’azapeptide CP-3(iv) (289 nmol/kg) ou le véhicule (NaCl 0,9%) de manière quotidienne par voie sous-cutanée (s.c.), et dans la deuxième étude avec l’UAG (100 nmol/kg), l’UAG6-13 (1000 et 3000 nmol/kg) ou le véhicule de manière biquotidienne par voie s.c. avant d’être soumises à une I/RM. Notre première étude a montré que le CP-3(iv) protège contre les dommages liés à l’I/RM par une réduction de la taille de l’infarctus et une préservation de l’hémodynamique cardiaque. Ces effets résultent en partie d’une augmentation du gène de l’adiponectine et des protéines impliquées dans sa transcription au niveau du tissu adipeux, conduisant à une augmentation des taux circulants de l’adiponectine et une réduction des concentrations plasmatiques des acides gras non estérifiés. Au niveau du myocarde, les propriétés anti- ii oxydatives, anti-apoptotiques et pro-métaboliques de l’adiponectine ont été observées. Aucun de ces effets n’a été observé chez les souris déficientes en CD36 et la récupération de la fonction cardiaque par le CP-3(iv) a été abrogée par un anticorps anti-adiponectine dans le modèle de cœur isolé, démontrant la dépendance du récepteur CD36 et l’importance du rôle de l’adiponectine pour médier les effets cardioprotecteurs du CP-3(iv). Notre deuxième étude a montré que l’UAG et l’UAG6-13 ont réduit le pourcentage de lésions myocardiques et préservé l’hémodynamique cardiaque. Ces effets résultent en grande partie par une diminution des concentrations plasmatiques des cytokines pro-inflammatoires IL-6 et TNF-α. De plus, nos résultats ont montré une diminution de l’apoptose et une activation de la voie AMPK impliquée dans l’oxydation des acides gras au niveau du cœur. Les effets de l’UAG6-13 sont indépendants du récepteur de la ghréline comme démontré par l’ajout concomitant de la D-Lys3-GHRP-6, un antagoniste du récepteur de la ghréline, dans le modèle de cœur isolé. En conclusion, les travaux de cette thèse ont montré que les peptides CP-3(iv) et UAG6- 13 possèdent des effets cardioprotecteurs puissants dans la pathologie de l’I/RM et constituent de nouvelles approches thérapeutiques pouvant être appliquées dans les maladies cardiovasculaires ischémiques. Mots-clés : Sécrétagogues de l’hormone de croissance, CD36, ghréline désacylée, ischémie/reperfusion du myocarde, adiponectine, récepteur de la ghréline iii Abstract Growth hormone-releasing peptides (GHRP) are synthetic peptides that stimulate growth hormone (GH) secretion after binding with the ghrelin receptor (previously known as the growth hormone secretagogue receptor 1a, GHS-R1a). Unacylated ghrelin (UAG) represents the predominant form of ghrelin in circulation, but UAG does not bind to the ghrelin receptor and does not stimulate GH release. Studies have shown that GHRPs and UAG possess cardioprotective effects independent from GH secretion. The group of Ong has identified the CD36 receptor, expressed in cardiomyocytes, macrophages and adipocytes among other cells, as the second binding site for GHRPs, whereas the receptor for UAG is still unknown until this day. The general aim of this thesis was to evaluate the cardioprotective effects of a new class of GHRPs analogues, the azapeptides, which show a higher selectivity towards the CD36 receptor in comparison to that of ghrelin, and the cardioprotective effects of a bioactive peptide fragment of UAG, UAG6-13, in the pathology of ischemic heart disease. The model of myocardial ischemia/reperfusion (MI/R) was generated by a surgical ligation of the left anterior descending coronary artery for 30 min to induce an ischemia, followed by a reperfusion of 6 or 48 h in C57BL/6 male mice. The mice have been pretreated in the first study with azapeptide CP-3(iv) (289 nmol/kg) or the vehicle (0.9% NaCl) daily by subcutaneous (s.c.) injection, and in the second study with UAG (100 nmol/kg), UAG6-13 (1000 nmol/kg and 3000 nmol/kg) or the vehicle twice daily by s.c. injection prior to being subjected to MI/R. Our first study have shown that CP-3(iv) protects against I/RM induced injury by reducing the infarct size and preserving myocardial hemodynamics. These effects result, in part, by an increase in adiponectin production/secretion and proteins involved in its transcription in adipose tissue. This leads to an increase in circulating levels of adiponectin and a decrease in plasma concentration of non-esterified fatty acids. In the myocardium, the anti-oxidative, anti-apoptotic and pro-metabolic properties of adiponectin has been observed. None of these effects was observed in CD36 deficient mice and the function recovery of the heart by CP-3(iv) has been abrogated by an anti-adiponectin antibody in an isolated heart model, showing the dependency for the CD36 receptor and the importance of the role of adiponectin to mediate the iv cardioprotective effects of CP-3(iv). Our second study showed that UAG and UAG6-13 have reduced the percentage of myocardial lesions and preserved cardiac hemodynamics. These effects result largely by a reduction in plasma concentration of pro-inflammatory cytokines IL- 6 and TNF-α. Moreover, our results have shown a reduction in apoptosis and an activation of the AMPK pathway involved in fatty acids oxidation in the heart. The effects of UAG6-13 are independent of the ghrelin receptor as shown by a concomitant addition of D-Lys3-GHRP-6, a ghrelin receptor antagonist, in the model of isolated heart. In conclusion, the work conducted in this thesis have shown that CP-3(iv) and UAG6-13 possess potent cardioprotective effects in the pathology of MI/R and constitute new therapeutic approaches which can be applied in ischemic cardiovascular disease. Keywords : Growth hormone secretagogues, CD36, unacylated ghrelin, myocardial ischemia/reperfusion, adiponectin, ghrelin receptor v Table des matières Résumé .................................................................................................................................. ii Abstract..................................................................................................................................iv Table des matières ..................................................................................................................vi Liste des tableaux .................................................................................................................... x Liste des figures .....................................................................................................................xi Liste des abréviations .......................................................................................................... xiii Remerciements .................................................................................................................. xxvii Chapitre 1 : INTRODUCTION ........................................................................................... 1 1. Historique de la découverte des sécrétagogues de l’hormone de croissance.......................... 2 1.1 Le récepteur CD36 .......................................................................................................
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