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Die Auswirkung der systemischen Applikation von 100µg/kg/KG rekombinantem speziesspezifischem Wachstumshormon (GH) über 26 Tage auf den Knochenumbau des Yucatan-Minischweins wurde an Wirbelkörpern, Beckenkämmen und Rippen histomorphometrisch untersucht. Der Einfluss der Distraktionsosteogenese auf die Mineralappositionsrate wurde ermittelt. 24 Tiere wurden an der linken Tibia osteotomiert, ein Fixateur externe wurde zur Distraktionsosteogenese von 2mm/d angelegt. 12 Tiere erhielten Wachstumshormon, 12 Placebo. Eine polychrome Fluoreszenzmarkierung wurde i.v. appliziert. Post mortem wurden Schnitte und Dünnschliffe der genannten Knochen angefertigt. Mittels Bildanalysesystem erfolgte die histomorphometrische Auswertung anhand der Parameter Knochendichte, Porosität, Trabekeldicke, Trabekelumbauparameter und Mineralappositionsrate (MAR). Signifikante Veränderungen durch Wachstumshormongabe konnten gezeigt werden. Unterschiede zwischen den Lokalisationen traten auf. So war die Knochendichte der GH-Tiere an Wirbelkörpern und Rippen signifikant geringer als in der Placebogruppe, kein signifikanter Unterschied zeigte sich am Beckenkamm. An allen 3 Lokalisationen war in der Wachstumshormongruppe eine signifikant erhöhte kortikale Porosität zu finden. Nur am Wirbelkörper waren die trabekuläre Knochendichte und die Trabekeldicke bei den GH-Tieren signifikant geringer als bei den Kontrolltieren. Die Knochenresorption war in der GH-Gruppe am Beckenkamm signifikant erhöht. Die Formation war bei den GH-Tieren sowohl iliakal als auch vertebral signifikant erhöht. Insgesamt ergab sich damit ein signifikant verminderter Anteil an ruhender Oberfläche bei den GH-Tieren. In ihrer Ausprägung waren diese Parameter zwischen Wirbel und Beckenkamm signifikant verschieden. Die MAR war in der GH-Gruppe signifikant höher als in der Placebogruppe, außerdem war sie während der Distraktionsphase signifikant höher als während der Konsolidierungsphase. Vergleicht man die Parameter mit Angaben aus der Literatur, kann bestätigt werden, dass die hier verwendeten Messmethoden geeignet sind, und dass das Yucatan-Minischwein ein geeignetes Modell zur Klärung von Fragestellungen der Knochenbiologie auch im Hinblick auf den Vergleich zum Menschen darstellt. / The effect of systemic application of 100 µg/kg recombinant species specific growth hormone (GH) on the bone remodelling of 24 Yucatan mini pigs for a duration of 26 days was evaluated on vertebral body, iliac crest, and rib. The influence of distraction osteogenesis on the mineral apposition rate (MAR) was examined. 24 animals were osteotomized at the left tibia and treated with an external fixator for distraction osteogenesis of 2 mm/d. 12 of them received GH, the others placebo. A sequential polychrome fluorescent labelling was applied. After sacrifice thin and ground sections were manufactured. Using an image analysis system, a histomorphometrical evaluation was performed by means of bone density, porosity, trabecular thickness, trabecular remodelling parameters, and mineral apposition rate (MAR). Significant changes after GH application were visible. Differences between the locations were found. The bone density of vertebrae and ribs of the treatment group was significantly lower than that of the placebo group, whereas no difference was seen in the iliac crest biopsies. All 3 locations showed a significantly higher cortical porosity in the GH group. The trabecular bone density and the trabecular thickness were significantly decreased only in the vertebral bodies of the treatment group. The bone resorption was significantly elevated in the iliac crests of the GH group. The bone formation was increased in the iliac crest as well as in the vertebrae of the GH treated animals. Therefore, the resting surface was significantly decreased in the GH group. The extent of these effects was significantly different between iliac crest and vertebral body. The MAR was significantly higher in the GH group and during distraction osteogenesis. Compared to results of other study groups these parameters validate the methods of measurement and show that the Yucatan mini pig is a suitable model for research concerning bone biology, especially concerning the comparison with human parameters.

Wachstumshormon (GH) besteht aus 191 Aminosäuren, hat eine Molekülmasse von 22kD und ist essentiell für postnatales Wachstum. Es wird aus der Adenohypophyse freigesetzt. GH bindet an einen GH-Rezeptor (GHR) und aktiviert somit über intrazelluläre Signalvorgänge Zielgene, insbesondere das, welches für die Kodierung von insulin-like growth factor (IGF-1) zuständig ist. IGF-1 vermittelt den Großteil aller GH-Signale. Zusammen mit den bereits bekannten GH Mutanten R77C und D112G ist in dieser Studie der neue GH Mutant d188-190 charakterisiert worden. Alle drei Mutanten wurden in heterozygoter Form in kleinwüchsigen Patienten identifiziert. Diesen Patientendaten zu Folge schien es möglich, dass d188-190 eine GH-antagonistische Wirkung besitzt. Zusätzlich wurde die extrem konservierte C-terminale Disulfidbrücke des GH im Mutanten d188-190 unterbrochen vorgefunden. Die Auswirkung der Unterbrechung wurde durch Substitution einer oder beider involvierter Cysteine durch Alanine untersucht. Alle Mutanten und Wildtypen des GH wurden in menschlichen embryonalen Nierenzellen (HEK-293) angezüchtet und eine Reihe von in vitro Experimenten sind für deren Charakterisierung etabliert worden. Es zeigte sich, dass d188-190 keine GH-antagonistische Wirkung besitzt. Im Vergleich zum Wildtyp weist der Mutant eine verminderte Bindungsaffinität zu GH, schwächere biologische Aktivität und höhere Stabilität auf. R77C und D112G sind dem Wildtyp GH sehr ähnlich. Die Disulfidbrücke ist wichtig für die Rezeptorbindung und für die biologische Aktivität von GH. Wenn ein Cystein entfernt wird vermindert sich die Stabilität des Moleküls. Dieser Effekt kann durch Entfernen des zweiten Cysteins wieder rückgängig gemacht werden. Die in dieser Studie etablierten Experimente können Verwendung finden in der Charakterisierung bislang nicht bekannter GH Mutanten und können darüber hinaus zur Behandlung von Patienten eingesetzt werden. / Growth hormone (GH) is a 22 kD, 191-aa, pituitary-derived peptide hormone that is essential for postnatal growth. GH signals via binding to GH receptor (GHR), which initiates intracellular signal transduction pathways. This leads to activation of target genes, most importantly the one encoding insulin-like growth factor (IGF)-1, which mediates most GH action. In this study a novel GH mutant, d188-190, was characterized along with previously reported GH mutants R77C and D112G. All of these mutants had been identified in heterozygous form in patients with retarded growth. Based on patient data, d188-190 was thought to be a GHR antagonist. Moreover, the extremely conserved C-terminal disulfide bridge of GH was disrupted in mutant d188-190 and its role was studied by substituting one or both of the involved cysteines with alanines. All mutants and wild type (wt) GH were produced in human embryonic kidney (HEK)-293 cells and an array of in vitro experiments was established for their characterization. It turned out that the novel d188-190 mutant is not a GHR antagonist after all. It has a diminished binding affinity to GHR, low biological activity and high stability compared to wt GH. R77C and D112G are rather similar to wt GH. The disulfide bridge is important for receptor binding and biological activity of GH. If one of the cysteines is removed the stability of the molecule drops but this can be reversed by removing both cysteines. If further GH mutants are to be identified, the established array of experiments will be useful for their fast characterization and could even contribute to correct treatment of patients.

A ghrelina, hormônio secretado principalmente por células gástricas, liga-se ao seu receptor, o receptor de secretagogo de GH (GHSR - Growth hormone secretagogue receptor), localizado no hipotálamo e na hipófise, estimulando a síntese e secreção do GH. Recentemente foram identificadas mutações no gene GHSR em crianças com baixa estatura idiopática (BEI) e com deficiência isolada de GH (DGH). No presente estudo investigamos a presença de mutações no gene GHSR em crianças com DGH isolada de causa não identificada e crianças com BEI, incluindo um subgrupo de crianças com atraso constitucional de crescimento e desenvolvimento (ACCD). Foram selecionados 14 pacientes com deficiência isolada de GH sem alterações anatômicas da região hipotálamo-hipofisária e 96 pacientes com BEI, destes 31 (32%) apresentavam ACCD. Também foram estudados 150 controles adultos e 197 crianças controle com crescimento e puberdade normais. A região codificadora do GHSR foi amplificada utilizando-se oligonucleotídeos iniciadores específicos, seguida de purificação enzimática e seqüenciamento automático. Encontramos 6 variantes alélicas em heterozigose no GHSR: nenhuma delas presente nos controles estudados, e quatro destas variantes estão localizadas em regiões conservadas do gene. Uma variante foi encontrada em uma paciente do grupo DGH (p.Val249Leu) e as outras cinco (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) foram encontradas em pacientes do subgrupo ACCD do grupo BEI. As variantes missense foram submetidas a estudo funcional que evidenciou que as mutações p.Ser84Ile e p.Val182Ala possuem diminuição na atividade basal associadas à diminuição da expressão do receptor na superfície celular. Adicionalmente, a mutação p.Ser84Ile também apresenta redução na atividade do GHSR induzida pelo ligante. A variante p.Val249Leu foi encontrada em uma paciente do sexo feminino com diagnóstico de DGH isolado. A falta de segregação familiar associada à ausência de déficit funcional da variante nos estudos in vitro sugere que, neste caso, a variante p.Val249Leu não é a causa do fenótipo de DGH nesta família e trata-se de uma variante alélica rara. As 5 variantes alélicas no GHSR (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) encontradas nos pacientes com BEI foram identificadas apenas naqueles com puberdade atrasada, ou seja, pertencentes ao subgrupo ACCD (3 do sexo masculino e 2 do sexo feminino). A freqüência de variantes neste grupo de pacientes foi de 16%, significativamente maior que nos outros grupos, e a ausência de variantes gênicas novas no grupo de crianças obesas com altura normal e mesmo no grupo de crianças com BEI sem ACCD sugere que nosso achado não foi casual e que as alterações descritas podem estar associadas ao fenótipo de ACCD. Os estudos in vitro mostraram prejuízos funcionais em 2 destas variantes (p.Ser84Ile e p.Val182Ala) porém, devido à limitação dos estudos funcionais (celulas heterólogas) não podemos afastar que as demais não tenham algum impacto funcional in vivo. Em conclusão, nossos resultados sugerem um envolvimento dos defeitos no GHSR na etiologia do atraso constitucional do crescimento e desenvolvimento em uma parcela de pacientes com esta condição / Ghrelin, hormone secreted by gastric cells, stimulates growth hormone secretion by acting on its receptor GHSR, located in the hypothalamus and pituitary. Recently, mutations in the GHSR gene were described in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). In the present study we analyzed the GHSR gene in patients with isolated GHD and patients with ISS, including a subgroup of patients with constitutional delay of growth and puberty (CDGP). We studied 14 GHD patients with normal pituitary magnetic resonance imaging and 96 patients with ISS, 31 of them with CDGP. We also studied 150 adults and in 197 children with normal stature. The entire coding region as well as the exon-intron boundaries of GHSR were PCR amplified in all patients and control group and PCR products were bidirectionally sequenced. Six different heterozygous variants in GHSR were identified: none of them were found in the control group and four of these amino acid substitutions occurred at a conserved position within the GHSR. One variant (p.Val249Leu) was found in a GHD patient and the other five (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were found in patients with CDGP. The missense variants were submitted to functional studies. Two of these variants (p.Ser84Ile and p.Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. The p.Val249Leu variant, found in a female patient with isolated GHD, did not segregate with the phenotype in the family and had no functional impairment in vitro. This suggests that p.Val249Leu is not the cause of the GHD in the family and may be a rare allelic variant. The other variants (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were identified only in patients with CDGP (3 male and 2 female). The frequency of allelic variants observed in this group (16%) was higher than expected by chance in contrast with ISS and GHD children, and the absence of other GHSR mutations in the large group of control children suggests that the association between GHSR mutations and CDGP phenotype is unlikely to be fortuitous. Functional studies revealed that two of the identified missense variants (p.Ser84Ile and p.Val182Ala) are functionally significant. These functional studies were performed in heterologous cell expression systems; therefore it is not possible to completely rule out that the other identified variants might cause some unrevealed impairment on GHSR function or expression in vivo. In conclusion, our data raise the possibility that abnormalities in ghrelin receptor function may be implicated in the ethiology of CDGP in some patients

A ghrelina, hormônio secretado principalmente por células gástricas, liga-se ao seu receptor, o receptor de secretagogo de GH (GHSR - Growth hormone secretagogue receptor), localizado no hipotálamo e na hipófise, estimulando a síntese e secreção do GH. Recentemente foram identificadas mutações no gene GHSR em crianças com baixa estatura idiopática (BEI) e com deficiência isolada de GH (DGH). No presente estudo investigamos a presença de mutações no gene GHSR em crianças com DGH isolada de causa não identificada e crianças com BEI, incluindo um subgrupo de crianças com atraso constitucional de crescimento e desenvolvimento (ACCD). Foram selecionados 14 pacientes com deficiência isolada de GH sem alterações anatômicas da região hipotálamo-hipofisária e 96 pacientes com BEI, destes 31 (32%) apresentavam ACCD. Também foram estudados 150 controles adultos e 197 crianças controle com crescimento e puberdade normais. A região codificadora do GHSR foi amplificada utilizando-se oligonucleotídeos iniciadores específicos, seguida de purificação enzimática e seqüenciamento automático. Encontramos 6 variantes alélicas em heterozigose no GHSR: nenhuma delas presente nos controles estudados, e quatro destas variantes estão localizadas em regiões conservadas do gene. Uma variante foi encontrada em uma paciente do grupo DGH (p.Val249Leu) e as outras cinco (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) foram encontradas em pacientes do subgrupo ACCD do grupo BEI. As variantes missense foram submetidas a estudo funcional que evidenciou que as mutações p.Ser84Ile e p.Val182Ala possuem diminuição na atividade basal associadas à diminuição da expressão do receptor na superfície celular. Adicionalmente, a mutação p.Ser84Ile também apresenta redução na atividade do GHSR induzida pelo ligante. A variante p.Val249Leu foi encontrada em uma paciente do sexo feminino com diagnóstico de DGH isolado. A falta de segregação familiar associada à ausência de déficit funcional da variante nos estudos in vitro sugere que, neste caso, a variante p.Val249Leu não é a causa do fenótipo de DGH nesta família e trata-se de uma variante alélica rara. As 5 variantes alélicas no GHSR (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) encontradas nos pacientes com BEI foram identificadas apenas naqueles com puberdade atrasada, ou seja, pertencentes ao subgrupo ACCD (3 do sexo masculino e 2 do sexo feminino). A freqüência de variantes neste grupo de pacientes foi de 16%, significativamente maior que nos outros grupos, e a ausência de variantes gênicas novas no grupo de crianças obesas com altura normal e mesmo no grupo de crianças com BEI sem ACCD sugere que nosso achado não foi casual e que as alterações descritas podem estar associadas ao fenótipo de ACCD. Os estudos in vitro mostraram prejuízos funcionais em 2 destas variantes (p.Ser84Ile e p.Val182Ala) porém, devido à limitação dos estudos funcionais (celulas heterólogas) não podemos afastar que as demais não tenham algum impacto funcional in vivo. Em conclusão, nossos resultados sugerem um envolvimento dos defeitos no GHSR na etiologia do atraso constitucional do crescimento e desenvolvimento em uma parcela de pacientes com esta condição / Ghrelin, hormone secreted by gastric cells, stimulates growth hormone secretion by acting on its receptor GHSR, located in the hypothalamus and pituitary. Recently, mutations in the GHSR gene were described in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). In the present study we analyzed the GHSR gene in patients with isolated GHD and patients with ISS, including a subgroup of patients with constitutional delay of growth and puberty (CDGP). We studied 14 GHD patients with normal pituitary magnetic resonance imaging and 96 patients with ISS, 31 of them with CDGP. We also studied 150 adults and in 197 children with normal stature. The entire coding region as well as the exon-intron boundaries of GHSR were PCR amplified in all patients and control group and PCR products were bidirectionally sequenced. Six different heterozygous variants in GHSR were identified: none of them were found in the control group and four of these amino acid substitutions occurred at a conserved position within the GHSR. One variant (p.Val249Leu) was found in a GHD patient and the other five (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were found in patients with CDGP. The missense variants were submitted to functional studies. Two of these variants (p.Ser84Ile and p.Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. The p.Val249Leu variant, found in a female patient with isolated GHD, did not segregate with the phenotype in the family and had no functional impairment in vitro. This suggests that p.Val249Leu is not the cause of the GHD in the family and may be a rare allelic variant. The other variants (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were identified only in patients with CDGP (3 male and 2 female). The frequency of allelic variants observed in this group (16%) was higher than expected by chance in contrast with ISS and GHD children, and the absence of other GHSR mutations in the large group of control children suggests that the association between GHSR mutations and CDGP phenotype is unlikely to be fortuitous. Functional studies revealed that two of the identified missense variants (p.Ser84Ile and p.Val182Ala) are functionally significant. These functional studies were performed in heterologous cell expression systems; therefore it is not possible to completely rule out that the other identified variants might cause some unrevealed impairment on GHSR function or expression in vivo. In conclusion, our data raise the possibility that abnormalities in ghrelin receptor function may be implicated in the ethiology of CDGP in some patients

La maladie cardiaque ischémique, la plus commune des maladies qui affectent le cœur, est encore aujourd’hui une importante cause de décès dans les pays industrialisés. Une réponse cardio-métabolique inflammatoire à un changement aigu initié par une modification du métabolisme énergétique du cœur ischémique est accentuée après que l’apport en oxygène ait été rétabli. Parmi les altérations délétères dans le myocarde qui en résultent, sont inclus l’accumulation d’acides gras non estérifiés (AGNE) ainsi que leur oxydation au détriment de l’utilisation du glucose, ce qui amplifie la génération d’espèces réactives de l’oxygène (ROS). Les tissus en périphérie du cœur tel que le tissu adipeux peuvent affecter l’étendue des blessures au myocarde par la relâche en circulation de substances bioactives comme les AGNE et l’adiponectine. Le CD36 est le principal facilitateur de l’entrée d’AGNE dans le cœur et les adipocytes et constitue une importante cible métabolique spécialement lors d’un stress d’ischémie-reperfusion (I/R). Il a été rapporté précédemment par notre groupe qu’un ligand synthétique et sélectif envers le CD36 exerce un effet protecteur puissant sur le système vasculaire. Cependant, aucune étude in vivo n’a rapporté d’effet cardioprotecteur de ligands sélectifs envers le CD36. Ainsi, ce projet visait à évaluer le rôle et possiblement l’effet cardioprotecteur de ligands sélectifs du récepteur CD36 sur la blessure au myocarde en I/R. Des souris CD36+/+ et CD36-/- ont été traitées quotidiennement avec le EP 80317, le CP-3(iv) ou le véhicule pendant 14 jours avant de subir la ligature temporaire de l’artère coronaire antérieure descendante gauche (LAD). Notre première étude a montré que le EP 80317 exerce un effet cardioprotecteur puissant tel que montré par la réduction de la surface des lésions et l’amélioration de la fonction cardiaque in vivo suivant la blessure au myocarde en I/R. De plus, le EP 80317 a réduit l’internalisation totale d’AGNE dans le myocarde, mesurée in vivo par l’imagerie métabolique cardiaque, en accord avec la diminution du niveau circulant d’AGNE. Une réduction de la lipolyse révélée par une perfusion de radiotraceur de palmitate et une augmentation du niveau d’expression de gènes adipogéniques et anti-lipolytiques appuient davantage l’effet du EP 80317 dans la prévention de la mobilisation délétère d’acides gras du tissu adipeux. Notre deuxième étude a investigué le mécanisme cardioprotecteur d’une nouvelle génération de ligands dotés d’une plus grande affinité de liaison envers le CD36. Cette étude a montré que le CP-3(iv) est aussi pourvu d’un puissant effet cardioprotecteur comme le montre la réduction de la taille de l’infarctus et l’amélioration de la fonction cardiaque post-I/R du myocarde qui est fonction d’une signalisation métabolique et anti-oxydante de l’adiponectine. En effet, l’augmentation des principales voies de signalisation régulant la sécrétion de l’adiponectine et des gènes antioxydants a été démontrée dans le tissu adipeux suivant l’I/R du myocarde et un traitement avec le CP-3(iv). L’activation de la protéine kinase B ou Akt dans le myocarde avec la diminution de la génération de ROS et de la signalisation de mort cellulaire appuient davantage le rôle cardioprotecteur du CP-3(iv) dans l’I/R du myocarde. En conclusion, le travail présenté dans cette thèse soutient qu’une signalisation du CD36 par le EP 80317 et le CP-3(iv) pourrait s’avérer être une nouvelle approche thérapeutique dans le traitement de la maladie cardiaque ischémique. Ces ligands synthétiques sélectifs envers le CD36 provoquent un effet salutaire sur le myocarde ischémique par le biais d’une amélioration du profil métabolique dans les premières heures de la reperfusion. Le EP 80317 réduit le niveau délétère d’AGNE et leur internalisation dans le cœur en situation d’excès, tandis que le CP-3(iv) augmente le niveau bénéfique d’adiponectine et son effet cardioprotecteur. / Ischaemic heart disease, the most common cause of heart disease, is still today a leading cause of mortality in industrialized countries. An inflammatory cardiometabolic response to acute changes elicited by energetic substrate shift in the ischemic heart is amplified once the oxygen supply is reinstated. Resulting deleterious alterations include increased myocardial accumulation of non-esterified fatty acids (NEFA) and their oxidation at the expense of glucose, thus enhancing reactive oxygen species (ROS) generation. Peripheral tissues such as the adipose tissue can affect the extent of myocardial injury by releasing bioactive substances such as adiponectin and NEFA into the circulation. CD36 is the main facilitator of the entry of NEFA in the heart or adipocytes and constitutes an important metabolic target especially during an ischaemia-reperfusion (I/R) stress. It was previously reported by our group that a selective synthetic ligand of CD36 exerts potent protective effects on the vasculature. However, no study has reported the in vivo cardioprotective effects of selective CD36 ligands. Thus, this project aimed to evaluate the role and possibly cardioprotective effects of selective CD36 receptor ligands on myocardial I/R injury. CD36+/+ and CD36-/- mice were pretreated with EP 80317, CP-3(iv) or vehicle for 14 days prior to undergoing a transient occlusion of the left anterior descending (LAD) coronary artery. Our first study showed that EP 80317 exerted potent cardioprotective effects as shown by reduced lesion area and ameliorated cardiac function following in vivo myocardial I/R injury. Furthermore, EP 80317 reduced total myocardial NEFA uptake, as assessed by in vivo metabolic cardiac imaging, in agreement with reduced levels of circulating NEFA. Reduced lipolysis revealed by palmitate radiotracer infusion and increased expression levels of adipogenic and anti-lipolytic genes further support an effect of EP 80317 in preventing deleterious fatty acid mobilization from adipose tissue. Our second study investigated the cardioprotective mechanisms of a new generation of ligands with increased affinity towards CD36. This study showed that CP-3(iv) is also endowed of potent cardioprotective effects as shown by reduced infarct area and improved myocardial function following myocardial I/R injury which is mediated by an adiponectin metabolic and anti-oxidative signaling pathway. Indeed, main signaling pathways regulating adiponectin secretion and antioxidative genes were shown to be increased in adipose tissue following myocardial I/R and CP-3(iv) treatment. Myocardial protein kinase B or Akt activation along with reduced ROS generation and cell death signaling further support a cardioprotective role of CP-3(iv) in MI/R. In conclusion, work from this thesis support that CD36 signaling by EP 80317 and CP-3(iv) may constitute a novel therapeutic approach for the treatment of ischemic heart disease. These synthetic CD36 selective ligands provoke salutary effects on ischaemic myocardium by means of an ameliorated metabolic profile in the first hours of reperfusion. EP 80317 reduces deleterious NEFA levels and their uptake into the heart in time of excess, while CP-3(iv) increases beneficial adiponectin level and its cardioprotective effects.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

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