Les récepteurs activés par les proliférateurs de peroxysomes (PPARs) sont des facteurs de transcription impliqués dans la régulation du métabolisme lipidique et de la tolérance au glucose. Les PPARs contrôlent également l’inflammation associée à de multiples pathologies, dont la polyarthrite rhumatoide. Dans les travaux présentés dans ce manuscrit, nous avons comparé les potentialités anti-arthritiques, dans un modèle expérimental, de deux agonistes synthétiques de haute affinité pour deux isotypes de PPARs, PPARα et PPARγ. Nous avons démontré qu’un traitement avec un agoniste sélectif de PPARγ, la pioglitazone, en plus de diminuer la sévérité de l’arthrite expérimentale, réduisait la perte osseuse inflammatoire en préservant la micro-architecture osseuse. Nous avons mis en évidence que PPARγ, d’une part, régulait l’expression locale et systémique de l’interleukine-17 et de RANKL, et que, d’autre part, il inhibait l’expression du facteur de transcription RORγt, acteur majeur de la voie IL-17/Th17. Les animaux déficients pour PPARγ nous ont permis de confirmer son rôle majeur dans le développement du processus arthritique. En effet, ces animaux présentent tous et de façon spontanée une arthrite associée à une augmentation du nombre de mastocytes capables de produire l’IL-17 et leur propre facteur de différenciation, le SCF dans la synoviale inflammatoire. Enfin, nous avons discuté le lien possible entre l'arthrite inflammatoire et la mastocytose à la lumière de l’étude d’un cas clinique d’un patient atteint de polyarthrite rhumatoïde concomitante à une mastocytose systémique / Peroxisome proliferator-activated receptors (PPARs) are transcription factors implicated in lipid metabolism and glucose tolerance. Once activated by specific agonists, PPARs control inflammation associated with numerous diseases, notably Rheumatoid arthritis. The first study presented here aim to compare the anti-arthritic potency of two high-affinity synthetic agonists for PPARα and PPARγ in an experimental model. Then we focused on the effect of pioglitazone, a high-affinity synthetic agonists for PPARγ, and demonstrated that a per os treatment with this agonist not only reduced experimental arthritis but also inhibited partly inflammation-related bone loss by preserving bone microarchitecture. We pointed out that PPARγ, on one hand, regulated local and systemic expression of interleukine-17 (IL-17) and RANKL and on the other hand, inhibited expression of transcription factor RORγt, a main regulator of IL-17/Th17 pathway. Study of mice deficient for PPARγ confirmed its major role in the development of the arthritic process since these mice developed spontaneously arthritis. Of interest arthritis in these mice is associated with increased number of synovial mast cells able to produce IL-17 and their own differenciation factor, the SCF. Finally, we discussed the possible link between inflammatory arthritis and mastocytosis in a case report of a patient suffering from rheumatoid arthritis concomitant to systemic mastocytosis

A metformina é uma droga utilizada para tratamento da diabetes tipo 2. O PPAR-α tem um papel central no controle imunometabólico. Portanto, o objetivo do estudo foi avaliar os efeitos imunometabólicos da dieta hiperlipídica (HFD), em camundongos C57BL6 (WT) e knockout para PPAR-α, tratados com metformina. Métodos: Os animais foram submetidos a uma HFD por 12 semanas, nos últimos dez dias de dieta os animais foram tratados com metformina. A oxidação de palmitato no músculo esquelético, As citocinas, no fígado, no tecido adiposo retroperitoneal, em hepatócitos e macrófagos intraperitoneais foram analisados. Resultados: O tratamento aumentou a oxidação de palmitado no músculo, promoveu um efeito anti-inflamatório no tecido adiposo e reverteu à inflamação dos macrófagos. No fígado e nos hepatócitos, a metformina causou um efeito inflamatório. Conclusão: A inflamação hepática foi induzida pelo tratamento e o efeito principal foi a um potencial aumento na inflamação nos hepatócitos. Os macrófagos tiveram uma resposta anti-inflamatória, assim como o tecido adiposo. / Metformin is a drug used to treatment of type 2 diabetes. PPAR-α plays a central role in immunometabolic control. Therefore, the aim of the study was to evaluate the effects of imumnometabolics of high fat diet (HFD) in C57BL6 mice (WT) and knockout for PPAR-α treated with metformin. Methods: The animals were subjected to a HFD for 12 weeks in the last ten days of diet the animals were treated with metformin. The palmitate oxidation in skeletal muscle, cytokines in the liver, in the retroperitoneal adipose tissue, hepatocytes and intraperitoneal macrophages were analyzed. Results: The treatment increased palmitate oxidation in muscle, it has promoted an anti-inflammatory effect in adipose tissue and macrophages to inflammation reversed. In the liver and hepatocytes, metformin caused an inflammatory effect. Conclusion: The liver inflammation was induced, and treatment was a main effect to a potential increase in inflammation in hepatocytes. Macrophages have an anti-inflammatory response, as well as adipose tissue.

As tiazolidinedionas (TZDs), ligantes sintéticos dos receptores nucleares PPARγ, têm sido amplamente utilizadas no tratamento da resistência à insulina, dislipidemias e síndrome metabólica. Estas drogas melhoram a homeostase da glicose promovendo redistribuição de gordura dos estoques viscerais para o subcutâneos, aumento da secreção de adiponectina, redução da lipemia, lipotoxicidade e da inflamação do tecido adiposo. Um estudo recente mostrou que o tratamento de ratos com a TZD rosiglitazona (RSG) induz um aumento na atividade dos complexos 1 e 2 da mTOR, que desempenham função importante no controle do metabolismo lipídico, adiposidade e função endócrina do tecido adiposo. Assim, o presente estudo teve como objetivo central elucidar o envolvimento especificamente do complexo 1 da mTOR de adipócitos nas alterações morfológicas, metabólicas e secretórias do tecido adiposo branco e marrom induzidas pela ativação farmacológica de PPARγ em camundongos. Para isto, camundongos com deleção de raptor (mTORC1) exclusivamente em adipócitos alimentados com dieta hiperlipídica foram tratados ou não com RSG (30 mg/kg/dia) por 8 semanas. Nossos dados mostraram que tanto o mTORC1 quanto o agonista de PPARγ são importantes reguladores da adiposidade, onde observamos que a deleção genética de mTORC1 em adipócitos conteve o aumento de adiposidade. Além disso, RSG mostrou-se eficente em reduzir a massa dos depósitos viscerais retroperitoneal a epididimal sem alterar o depósito subcutâneo inguinal. RSG aumentou significativamente a massa do tecido adiposo marrom, efeito esse que foi completamente abolido pela deficiência do complexo 1 da mTOR. Deficiência de mTORC1 em adipócitos promoveu aumento no conteúdo de UCP1 (expressão gênica e proteica), efeito este que não foi alterado pelo tratamento com RSG. Outros efeitos de RSG mostraram-se dependentes de mTORC1 como o aumento de frequência de adipócitos de menor área, aumento dos níveis de adiponectina e redução dos níveis de BCAA séricos, além da expressão gênica de CD36 e PEPCK, lipídeos mitocondriais como a cardiolipina e fosfatidiletanolamina e mediadores lipídicos como as ceramidas de cadeia longa no tecido adiposo branco. Por outro lado encontramos efeitos de RSG independentes de mTORC1, como a redução nos níveis séricos de TAG, redução de expressão gênica de fatores inflamatórios, tais como IL1 e TNF, NLRP3, DUSP6, além de PGC1 e FAS, insulina plasmática, melhora na homeostase glicêmica. Concluímos assim que mTORC1 em adipócitos é importante mediador de ações de agonista de PPARγ. / Thiazolidinediones (TZDs), synthetic ligands of nuclear receptors PPARγ, have been widely used in the treatment of insulin resistance, dyslipidemia and metabolic syndrome. These drugs improve glucose homeostasis by promoting redistribution of fat from visceral to subcutaneous depots, increasing adiponectin secretion, reducing lipemia, lipotoxicity, and inflammation of adipose tissue. A recent study showed that the treatment of rats with TZD rosiglitazone (RSG) induces an increase in the activity of mTOR complexes 1 and 2, which play an important role in the control of lipid metabolism, adiposity and endocrine function of adipose tissue. Thus, we investigated herein the specific involvement of adipocyte mTOR complex 1 in the morphological, metabolic and secretory alterations of white and brown adipose tissue induced by pharmacological activation of PPARγ in mice. For this, mice with raptor deletion (mTORC1) exclusively in adipocytes and littermate controls were fed a hyperlipidic diet and treated or not with RSG (30 mg/ kg/ day) for 8 weeks. Our data showed that both mTORC1 and PPARγ agonist are important adiposity regulators, where we observed that the genetic deletion of mTORC1 in adipocytes prevented the increase in adiposity. In addition, RSG was effective in reducing the masses of visceral fat depots retroperitoneal and epididymal without altering the mass of the subcutaneous fat depot inguinal. RSG induced an expressive increase in brown adipose tissue mass, such, an effect that was blocked by mTOR 1 complex deficiency. mTORC1 ablation in adipocytes increased UCP1 content (gene and protein expression). Interesting, RSG lost its ability to reduce the percentage of smaller adipocytes, to increase serum levels of adiponectin and reduce those of BCAA, as well as to increase mRNA levels of CD36 and PEPCK, mitochondrial lipids such as cardiolipin and phosphatidylethanolamine, lipid mediators as long chain ceramides in white adipose tissue. Other effects of RSG such as reducing serum TAG and insulin levels, adipose tissue inflammation, such as IL1 and TNF, and improving glucose homeostasis were not affected by mTOR complex 1 deficiency. We conclude thus that mTORC1 is important mediator of some actions of PPARγ agonism.

De part leur dimension élevée, les données de puces à ADN nécessitent l’application de méthodes statistiques pour en extraire une information pertinente. Dans le cadre de l’étude des différences entre deux agonistes de PPAR (Peroxisome Proliferator-Activated Receptor), nous avons sélectionné trois méthodes de sélection de variables : T-test, Nearest Shrunken Centroids (NSC) et Support Vector Machine – Recursive Feature Elimination. Ces méthodes ont été testées sur des données simulées et sur les données réelles de l’étude PPAR. En parallèle, une nouvelle méthodologie, MetRob, a été développée afin d’améliorer la robustesse ce ces méthodes vis à vis de la variabilité technique des puces à ADN, ainsi que leur reproductibilité. Cette nouvelle méthodologie permet principalement d’améliorer la valeur prédictive positive, c’est-à-dire la confiance accordée aux résultats. La méthode NSC s’est révélée la plus robuste et ce sont donc les résultats de cette méthode, associée à MetRob, qui ont été étudiés d’un point de vue biologique. / The microarray technology provides high dimensional data that need to be statistically treated for extracting relevant information. Within the context of the study of the differences between two PPAR (Peroxisome Proliferator-Activated Receptor) agonists, we selected three feature selection methods : T-test, Nearest Shrunken Centroids (NSC) and Support Vector Machine – Recursive Feature Elimination. These methods were tested on simulated and on real data. At the same time, a new methodology, MetRob, was developed in order to improve the robustness of these methods towards the technical variability of microarrays, as well as their reproducibility. This new methodology mainly improves the positive predictive value, which means the confidence in the results. The NSC method was found to be the most robust. The results of the association of MetRob and NSC were thus studied from a biological point of view.

Receptores ativados da proliferação de peroxissomos (PPAR) são receptores nucleares que regulam o metabolismo de gordura e glicose, adipogênese e polarização de macrófagos, e são os mediadores da ação de uma grande classe de fármacos usada no tratamento de diabetes tipo 2, as tiazolidinadionas (TZD). Enquanto as TZDs reduzem a glicose do sangue e aumentam efetivamente a sensibilidade à insulina, elas podem também apresentar efeitos colaterais como aumento do risco de complicações cardiovasculares, ganho de peso, retenção de fluido e toxicidade hepática. Por causa disso, novos fármacos que possuem respostas mais favoráveis devem ser desenvolvidos, e o mecanismo de ativação do PPAR por ligantes vem sendo intensamente examinado. Para entender a relação entre a ligação de agonistas ao PPAR e a ativação transcricional, pretendíamos primeiramente obter cristais de PPAR-LBD (domínio de ligação ao ligante) humano na forma apo. Porém, surpreendentemente, a análise do sítio de ligação ao ligante revelou a presença de três pequenas moléculas, identificadas como ácidos nonanoicos e octanoicos. Este trabalho reporta a análise da estrutura cristalográfica do PPAR LBD complexado simultaneamente com três ácidos graxos de cadeia média (AGCM), provindos de bactérias (organismo de expressão), localizados no sítio de ligação ao ligante. A análise estrutural e funcional sugere que os AGCM são agonistas parciais que estabilizam a conformação do LBD do PPAR por mecanismo independente da hélice 12. / PPARs (peroxisome proliferator activated receptors) are nuclear receptors that regulate glucose and fat metabolism, adipogenesis and macrophage polarization and mediate actions of a major class of drugs that are used to treat type 2 diabetes, the thiazolidinediones. While TZDs reduce blood glucose and improve insulin sensitivity effectively, they can also exhibit deleterious side effects such as increased cardiovascular risk, weight gain, fluid retention and liver toxicity. Because it is desirable to develop new PPAR drugs with more favorable spectrums of response, mechanisms of PPAR ligand activation have come under intense scrutiny. To understand relationships between PPAR ligand binding and transcriptional activation, we sought to obtain apo human PPAR-LBD (ligand binding domain) crystals that diffract to high resolution. More surprisingly, close analysis of the ligand binding pocket revealed the presence of three small molecules, identified as nonanoic acid and octanoic acid. Here, we report the X-ray structural analysis of the PPAR LBD complexed with three bacterial (expression organism) medium chain fatty acids (MCFAs) that simultaneously occupy the buried ligand binding pocket (LBP). Structural and functional analysis suggests that MCFAs are partial agonists that stabilize PPAR LBD conformation, through a helix 12 independent mechanism.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Certains antagonistes du récepteur AT1 (« angiotensin II type 1 receptors ») utilisés dans le traitement de l'hypertension artérielle ont par la suite également montré une activité au niveau de PPAR[gamma] (« Peroxisome Proliferator Activated Receptor [gamma] »), un récepteur impliqué dans la régulation du métabolisme du glucose. Cela constitue une nouvelle approche thérapeutique vers un traitement concomitant de l'hypertension artérielle et du diabète de type II, qui sont souvent associés. Dans ce contexte, nous nous sommes dirigés vers la conception rationnelle de molécules capables d'interagir à la fois sur les deux récepteurs impliqués dans ces affections. Pour cela, nous avons utilisé le concept de « designed multiple ligand » tel qu'il a été défini par certains chercheurs de l'Industrie pharmaceutique. Nous l'avons appliqué en combinant les pharmacophores propres aux antagonistes du récepteur AT1 et aux agonistes de PPAR[gamma], afin de générer une série diversifiée de composés. Afin de diriger la conception de ces molécules, nous avons par ailleurs réalisé des expérimentations de modélisation moléculaire (« docking ») sur PPAR[gamma]. Cela nous a conduits à développer une nouvelle méthode dans le but de prédire le caractère agoniste des composés étudiés. Enfin les molécules ont été évaluées pour leurs propriétés antagonistes AT1 et agoniste PPAR[gamma]. D'intéressantes relations structures activités ont été dégagées / Some angiotensin II-type 1 receptor (AT1) antagonists, used for blood pressure control, exhibit also an activity on peroxisome proliferator activated receptor [gamma] (PPAR[gamma]), which is involved in the control of glucose metabolism. Such compounds could be promising drugs for the treatment of both hypertension and type II diabetes, which are often concomitant. Therefore, we have rationally designed molecules potentially able to interact with both receptors involved in these diseases. We used the "design multiple ligands" concept, as previously developed by industrial pharmacists, to build up a diversified molecule set via combination of both pharmacophores of AT1 and PPAR[gamma] receptor antagonists and agonists, respectively. Molecular modeling experiments (docking) on PPAR[gamma] were conducted to rationalise the synthesis and allow us to predict in some extent the agonistic activity of the studied compounds

A inflamação é fundamental para a manutenção da homeostasia e para a resposta do organismo à injúria. A resposta inflamatória deve ser adequada aos estímulos agressores; no sistema nervoso central, sua inadequação conduz à gênese de diferentes doenças neurodegenerativas. A proteína anexina A1 (ANXA1) e os receptores ativados por proliferadores de peroxissomo (PPAR) controlam a inflamação, pois ambos inibem o desenvolvimento da inflamação e aceleram sua resolução. Nosso grupo de pesquisa tem mostrado que a ANXA1 modula a expressão de PPARγ em macrófagos. Assim, o presente trabalho investigou a modulação da expressão do PPARγ e das suas funções em células da microglia pela ANXA1. Foram empregadas células imortalizadas da linhagem BV2 (microglia murina), inalteradas ou transfectadas para redução da expressão de ANXA1, tratadas com ANXA1 exógena (recombinante - rANXA1) ou com agonista ou antagonista de PPARγ (pioglitazona e GW9662, respectivamente). Os resultados obtidos mostraram que: 1) tratamento com rANXA1 aumenta as expressões gênica (RT-PCR) e proteica (Western Blotting) de PPARγ, e ambas as expressões estão reduzidas em células com deficiência endógena de ANXA1, sendo que tal efeito foi revertido pela ação da rANXA1; 2) tratamento com rANXA1 não induz a expressão dos fatores de transcrição ligados a expressão de PPARγ: proteínas ligantes de elementos de resposta ao cAMP - CREB - e transdutores de sinais e ativadores de transcrição - STAT6 - (Western Blotting), mas os níveis de ambos os fatores estão reduzidos em células transfectadas, e tal efeito não foi revertido pelo tratamento com rANXA1; 3) tratamento com pioglitazona ou com rANXA1 individualmente aumenta a fagocitose de células PC12 apoptóticas (citometria de fluxo), mas o tratamento simultâneo não altera a fagocitose induzida por pioglitazona ou rANXA1; no entanto, tratamento com GW9662 inibiu a fagocitose induzida pelo tratamento com rANXA1; 4) o tratamento com rANXA1 aumenta a expressão de CD36 (citometria de fluxo); a expressão de CD36 está reduzida em células transfectadas e tal expressão não é revertida pelo tratamento com rANXA1. Em conjunto, os dados obtidos mostram a modulação da ANXA1 sobre PPARγ em células da micróglia, com possível ação sobre a fagocitose de células apoptóticas, e que a redução da expressão de ANXA1 reduz acentuadamente a expressão dos fatores de transcrição STAT6 e CREB, bem como a expressão de CD36. A elucidação dos efeitos resultantes destas alterações desencadeadas pela deficiência de ANXA1 endógena poderá contribuir para compreensão da fisiopatologia da neuroinflamação. / Inflammation is a key process in maintaining homeostasis and is essential for the body\'s response to injury. The inflammatory response must be proportional to the aggressor stimuli; in the central nervous system, a failed proper modulation leads to the development of different neurodegenerative diseases. Protein annexin A1 (ANXA1) and peroxisome proliferated-activated receptors (PPAR) control inflammation, as both inhibit development of inflammation and accelerate its resolution. Our research group has demonstrated that ANXA1 modulates PPARγ expression in macrophages. Thus, the present work investigated the modulation of PPARγ expression and its functions in microglia cells by ANXA1. In order to assess such, immortalized cells from cell line BV2 (murine microglia), either unadulterated or transfected for reduced expression of ANXA1, were treated with exogenous ANXA1 (recombinant protein - rANXA1) or either with PPARγ agonist or antagonist (pioglitazone and GW9662, respectively). The obtained results demonstrated that: 1) treatment with rANXA1 increases both gene (RT-PCR) and protein (Western Blotting) expressions of PPARγ, and also that both expressions are reduced in cells with endogenous deficiency of ANXA1, and such effect was reversed by the actions of rANXA1; 2) treatment with rANXA1 does not promote the expression of transcription factors associated with PPARγ expression: cAMP response element binding protein - CREB - and signal transductor and activator of transcription 6 - STAT6 (Western Blotting), but the expression levels of both factors are reduced in transfected cells, and such effect was not reversed by treatment with rANXA1; 3) individual treatment with pioglitazone or rANXA1 increases phagocytosis of apoptotic PC12 cells (flow cytometry), but simultaneous treatment does not affect pioglitazone/rANXA1-induced phagocytosis; however, treatment with GW9662 inhibited rANXA1-induced phagocytosis; 4) treatment with rANXA1 increases CD36 expression (flow cytometry); the expression of CD36 is reduced in transfected cells, and such expression is not reversed by treatment with rANXA1. The obtained data demonstrate the modulation ANXA1 exerts upon PPARγ in microglia cells, with a possible action upon phagocytosis of apoptotic cells, and that reduction of ANXA1 expression greatly reduces the expression of transcription factors STAT6 and CREB, as well as the expression of CD36. Elucidation of such effects that arise from a deficiency of endogenous ANXA1 will contribute to a better comprehension of the pathophysiology of neuroinflammation.

Les ligands des récepteurs nucléaires PPAR[gamma] (15-deoxy-[delta]12,14-Prostaglandine J2 (15d-PGJ2) et les thiazolidinediones (TZDs) : troglitazone (TGZ), ciglitazone (CGZ)) exercent un effet antiprolifératif sur les lignées cancéreuses mammaires. Plusieurs études suggèrent que les effets anticancéreux sont liés à des effets PPAR[gamma]-indépendants. Notre travail s?inscrit dans la compréhension de tels mécanismes d?action. Notre étude a montré une induction du facteur de transcription EGR1 (Early Growth Response gene 1) par certains ligands de PPAR[gamma] (TGZ, CGZ, 15d-PGJ2 et [delta]2-TGZ (agoniste inactif de PPAR[gamma])) dans les cellules cancéreuses mammaires hormono-dépendantes MCF7. Cet effet est précoce et PPAR[gamma]-indépendant. Il est lié à une libération quasi immédiate de calcium intracellulaire suivie de l?activation des ERK1/2. L?induction d?EGR1 a aussi lieu dans les cellules hormono-indépendantes MDA-MB-231 exposées à la [delta]2-TGZ. Cependant, l?induction d?EGR1 ne joue qu?un rôle partiel dans l?effet antiprolifératif. Les données d?une analyse par puce à ADN ont suggéré l?induction d?un stress du réticulum endoplasmique (RE) dans les cellules MCF7 exposées à la [delta]2-TGZ. Des analyses complémentaires ont confirmé que la [delta]2-TGZ induit un tel stress dans les cellules MCF7 et MDA-MB-231. Cependant, le rôle du stress du RE dans l?effet antiprolifératif de la [delta]2-TGZ reste à déterminer. Nous avons enfin testé l?hypothèse d?un lien entre EGR1 et stress du RE. En effet, EGR1 est aussi induit précocement par d?autres inducteurs de stress du RE. Les diverses situations où l?induction d?EGR1 est inhibée suggèrent une régulation possible de l?expression du facteur de transcription ATF3 par EGR1 / The ligands of PPAR[gamma] nuclear receptors (15-deoxy-[delta]12,14-Prostaglandin J2 (15d-PGJ2) and thiazolidinediones (TZDs) : troglitazone (TGZ), ciglitazone (CGZ)) show antiproliferative effects on breast cancer cell lines. Several studies suggest that the anti-cancer effects are PPAR[gamma]-independent. Our work is focused on the comprehension of such mechanisms of action. Our study has shown the induction of the transcription factor EGR1 (Early Growth Response gene 1) by some PPAR[gamma] ligands (TGZ, CGZ, 15d-PGJ2, and [delta]2-TGZ (PPAR[gamma] inactive agonist)) in the hormone-dependent breast cancer cells MCF7. This early effect is PPAR[gamma]-independent. It is associated with the almost immediate release of intracellular calcium followed by the activation of ERK1/2. EGR1 induction also occurs in the hormone-independent breast cancer cells MDA-MB-231 treated with [delta]2-TGZ. However, EGR1 induction plays only a partial role in the antiproliferative effect. Data analysis of DNA array has suggested the induction of an endoplasmic reticulum stress (ER) in MCF7 cells treated with [delta]2-TGZ. Complementary data have confirmed this result in MCF7 cells and in MDA-MB-231 cells. However, the role of ER stress in the antiproliferative effect is still to be determined. Finally, we have tested the hypothesis of a link between EGR1 and ER stress. Indeed, EGR1 is also early induced by other ER stress inductors. Diverse conditions where EGR1 is inhibited suggest a possible regulation of ATF3 expression by EGR1

Le Système Rénine Angiotensine tient une place prépondérante au sein de la circulation cérébrale. Les Antagonistes des Récepteurs AT1 à l'Angiotensine II (ARAII) ont prouvé leur efficacité dans la prévention de l'Accident Vasculaire Cérébral (AVC), indépendamment de leur effet anti-hypertenseur. Plusieurs mécanismes pourraient être impliqués dans cette cérébroprotection. D'une part, en bloquant les récepteurs AT1, les ARAII favorisent la stimulation des récepteurs AT2 à l'angiotensine II. Le caractère bénéfique lié à la stimulation des récepteurs AT2 s'oppose au caractère délétère lié à la stimulation des récepteurs AT1. Nous avons montré que cet équilibre AT1 - AT2 est modifié au niveau cérébrovasculaire suite à un régime hypersodé. En effet, la vasodilatation des artérioles cérébrales médiée par les récepteurs AT2 est abolie, ce qui pourrait constituer un élément délétère lors de la survenue d'un évènement ischémique. D'autre part, certains ARAII présentent une affinité pour les récepteurs PPAR-gamma. Cette activité, démontrée comme protectrice à différents niveaux vasculaires, pourrait également être bénéfique pour la circulation cérébrale. Nous avons en particulier montré que l'activation PPAR-gamma améliore les effets des ARAII au niveau de la circulation cérébrale (diamètre artériolaire, réactivité à l'angiotensine II). Les mécanismes en jeu semblent impliquer des modifications de la fonction des récepteurs AT1-AT2, indépendamment de leur expression. La stimulation des récepteurs AT2 et l'activation PPAR-gamma constituent donc deux propriétés particulières des ARAII. Ces propriétés pourraient participer au caractère cérébroprotecteur des ARAII, au-delà du seul blocage des récepteurs AT1. Le développement de molécules duales regroupant les activités antagoniste AT1 - agoniste PPAR-gamma pourrait constituer un avenir thérapeutique intéressant dans le traitement de l'hypertension en apportant une protection cérébrovasculaire supérieure aux traitements actuels / The Renin Angiotensin System plays a major role in cerebral circulation. AT1 receptor blockers (ARBs) afford protection against cerebrovascular complications that go beyond that to be expected from their blood pressure lowering action. Several mechanisms could explain such beneficial effects. Firstly, by blocking AT1 receptors, ARBs promote AT2 receptor stimulation by angiotensin II. The beneficial effect related to stimulation of AT2 receptors (vasodilation) counterbalances the deleterious actions of AT1 receptors stimulation. Changes in this ratio may then alter cerebral circulation. We demonstrated that the AT1- AT2 ratio is modified at the cerebrovascular level during high salt intake, which is a risk factor for stroke. The AT2-mediated vasodilation of pial arterioles is abolished. Secondly, some ARBs act as partial agonists of PPAR-gamma. Such an activity, which has been demonstrated to protect extracerebral vessels, could also be beneficial for cerebral circulation. Our results showed that PPAR-gamma activation improves ARB effects on cerebral circulation (arteriolar diameter, angiotensin II reactivity). The underlying mechanisms could imply functional regulation of AT1-AT2 receptors without any change in expression status. AT2 receptor stimulation and PPAR-gamma activity are two special properties of ARBs. These properties could contribute to the cerebroprotection induced by ARBs, beyond the AT1-receptor blockade. Development of new molecules with AT1-receptor blockade and PPAR-gamma activity could take part into the future therapeutic management of hypertension, providing a better cerebrovascular protection