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Myocardial infraction occurs when blood flow to destination of the heart muscle is insufficient. This decrease is due to partial or complete occlusion of coronary arteries by atherosclerotic plaque and/or thrombus. To ensure a flow rate adapted to the metabolic needs of the body, the heart changes its structure through a complex process called ventricular remodelling. Remodelling is characterized by a ventricular dilation, an hypertrophy of cardiomyocytes and the development of a reparative and reactive fibrosis. Initially beneficial, it eventually leads to ventricular dysfunction and heart failure. Cardiac fibroblasts represent 60-70% of the total cellular population of the heart. They play a fundamental role in cardiac physiology by ensuring the structural integrity of the heart through a controlled turnover of the extracellular matrix. After myocardial infarction, various stimuli lead to their proliferation and differentiation in hyper-metabolic cells (the myofibroblasts). Angiotensin II (AgII) and Transforming Growth Factor β (TGFβ) are key mediators of these processes. These molecules activate several signaling pathways (MAPK, Smad, RhoA/ROK, NADPH axidase) resulting in stimulation of profibrotic gene expression. Several studies have shown that AMP-activated protein kinase (AMPK) could interact with these pathways and control cellular processes such as proliferation/apoptosis and differentiation. In this work, we have studied the role of AMPK in human cardiac fibroblast myodifferentiation. Through the use of AMPK-α1 knockout mice (KO), we have also investigated the role of this protein kinase in vivo, in the development of fibrosis after myocardial infarction. These mice have been subjected to coronary ligation causing a myocardial infarction. The expression of fibrotic genes has been measured by qRT-PCR in the infarcted and the remote zone isolated from wild-type (WT) and KO hearts. Meanwhile, cardiac function has been assessed by echocardiography. We show increased expression of collagen I and III, “Plasminogen Activator Inhibitor-1 (PAI-1) and the “connective tissue factor (CTGF) in the infarcted region of hearts from KO mice versus WT mice (similar basal expression level). By contrast, there is no significant change of expression in the remote zone. By echocardiography, we show a greater ventricular dilation on KO mice, compared with WT mice. Our results argue for a protective role of AMPK as regards of cardiac fibrosis and remodelling and are consistent with the data obtained in cultured human cardiac fibroblasts. In this model, we show that TGFβ-1 changes cell morphology and increases to about twice the level of expression of the alpha isoform smooth muscle actin (α-SMA), a marker of myodifferentiation. Preincubation with the A-769662 compound, a pharmacological activator of AMPK, prevents these changes. Phosphorylation of Smad3 induced by TGF-β1 is also reduced in these conditions and could contribute to the anti-fibrotic affects of AMPK activation in the infarcted heart L’infarctus du myocarde survient lorsque le flux sanguin à destination du muscle cardiaque est insuffisant. Cette diminution est due à l’occlusion partielle ou complète des artères coronaires par une plaque d’athérosclérose et/ou d’un thrombus. Afin d’assurer un débit adapté aux besoins métaboliques de l’organisme, le cœur modifie sa structure par un processus complexe appelé remodelage ventriculaire. Le remodelage est caractérisé par une dilatation de la chambre ventriculaire, une hypertrophie des cardiomyocytes et le développement d’une fibrose cicatricielle et interstitielle. Initialement bénéfique, il finit par entraîner une dysfonction ventriculaire qui peut conduire à long terme à une insuffisance cardiaque chronique. Les fibroblastes cardiaques représentent 60-70 % de la population cellulaire du cœur. Ils jouent un rôle fondamental dans la physiologie cardiaque en assurant le maintien de l’intégrité structurale du cœur à travers une prolifération contrôlée et un turnover de la matrice extracellulaire. Après un infarctus du myocarde, divers stimuli entraînent leur prolifération et leur différenciation en cellules hyper-métaboliques (les myofibroblastes). L’ angiotensine II (AgII) et le «Transforming Growth Factor β» (TGFβ) sont des médiateurs clés de ces processus. Ces molécules activent plusieurs voies de signalisation (MAPK, Smad, RhoA/ROK, NADPH oxydase) qui aboutissent à la stimulation de l’expression des gènes profibrotiques. Plusieurs études ont montré que l’AMP-activated protein kinase (AMPK) pouvait interagir avec certains de ces éléments de signalisation et contrôler des processus cellulaires comme la croissance, la prolifération/différenciation et l’apoptose. Dans ce travail de mémoire, nous avons étudié le rôle de l’AMPK dans la myodifférenciation des fibroblastes cardiaques humains. Grâce à l’utilisation de souris transgéniques AMPK α1-knockout (KO), nous avons également investigué le rôle de cette protéine kinase in vivo, dans le développement de la fibrose myocardique post-infarctus. Ces souris ont été soumises à une ligature de la coronaire provoquant un infarctus du myocarde. L’expression de plusieurs gènes fibrotiques dans les régions saine et infarcie du ventricule gauche a été mesurée par qRT-PCR. Parallèlement, la fonction cardiaque a été évaluée par échocardiographie. Nous montrons une expression augmentée de collagène I et III, du «Plasminogen Activator Inhibitor-1 » (PAl-1) et du «Connective Tissue Factor» (CTGF) dans la région infarcie des cœurs de souris KO versus la région infarcie des cœurs de souris contrôles (WT) (niveau d’expression basal similaire). Par contre, il n’y a aucun changement significatif d’expression dans la région saine des souris WT et KO. Les résultats de l’analyse échocardiographique montrent une dilatation du ventricule plus importante chez les souris KO, par rapport aux souris WT. Ces résultats, en faveur d’un rôle protecteur de l’AMPK vis-à-vis de la fibrose et du remodelage, sont en accord avec les données obtenues in vitro, dans des cultures de fibroblastes cardiaques humains. Nous montrons que le TGFf3-l modifie la morphologie des cellules et augmente d’environ deux fois le niveau d’expression de l’isoforme alpha de l’actine musculaire lisse (αSMA), un marqueur de myodifférenciation. Une préincubation avec le composé A-769662, un activateur pharmacologique de 1’AMPK, empêche ces changements. La phosphorylation de Smad3 induite par le TGFβ- 1 est également diminuée dans ces conditions et pourrait contribuer aux effets anti-fibrotiques d’une activation de 1’AMPK dans le cœur infarci

Myocardial Infarction --- Heart --- Transforming Growth Factors

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Transforming Growth Factor beta. --- Transforming growth factors-beta.

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Transforming growth factors-beta --- GROWTH SUBSTANCES, congresses --- TRANSFORMING GROWTH FACTOR BETA, congresses --- Beta transforming growth factors --- TGF-beta (Peptide) --- Transforming growth factor beta --- Transforming growth factors --- Congresses. --- GROWTH SUBSTANCES --- TRANSFORMING GROWTH FACTOR BETA --- Growth substances --- Congresses

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Transforming growth factor-β (TGF-β) is a secreted polypeptide with multifunctional properties manifested during embryonic development, adult organ physiology, and pathobiology of major diseases, including cancer and fibrotic and cardiovascular diseases. The signaling pathway of TGF-β now is rather well understood. Continuing revelations in the mechanisms of action of TGF-β provide specific mechanistic examples of how human cells lose their controlled function and behave wrongly during the development of diverse diseases. Equally important, however, is the current promise of exploiting the TGF-β pathway in combating human disease. This book comprehensively covers major areas of human disease where the involvement of TGF-β is firmly established. Simultaneously, the book highlights major gaps in knowledge and the future directions of research that can benefit human medical science. The core set of diseases where TGF-β action is well documented and are included in the book are cancer and cardiovascular and fibrotic disorders. The central aim of the book is to stimulate young scientists to enter the prolific TGF-β field and find new solutions to the problems remaining in this area of study. For this purpose the book provides authoritative educational chapters that furnish a good introduction to the field for young doctoral students, postdocs, and clinical fellows. The book also serves as a valuable reference for the aficionados in the field, who can find accessible and well-illustrated material for their teaching and lecturing activities, via which the importance of TGF-β biology is disseminated to the world of science and to the public.

Cell differentiation. --- Cell proliferation. --- Transforming growth factors-beta. --- Biology --- Health & Biological Sciences --- Microbiology & Immunology --- Cytokines --- Pathophysiology. --- Beta transforming growth factors --- TGF-beta (Peptide) --- Transforming growth factor beta --- Life sciences. --- Cancer research. --- Cytokines. --- Growth factors. --- Cell biology. --- Life Sciences. --- Cytokines and Growth Factors. --- Cell Biology. --- Cancer Research. --- Cellular immunity --- Immune response --- Transforming growth factors --- Regulation

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Inhibin --- Inhibine --- #ABIB:aeco --- Biochemie --- Eiwitten --- Organische chemie --- Biochemie. --- Eiwitten. --- Organische chemie. --- Glycoproteins --- Hormones, Sex --- Peptide hormones --- Transforming growth factors-beta