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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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Coronary heart disease. --- Ventricular fibrillation. --- Fibrillation, Ventricular --- Arrhythmia --- Cardiac arrest --- Coronary arteries --- Coronary arteriosclerosis --- Coronary disease --- Coronary thrombosis --- Ischemic heart disease --- Myocardial ischemia --- Heart --- Type A behavior --- Diseases

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Myocardial tissue engineering (MTE), a strategy that uses materials or material/cell constructs to prolong patients’ life after cardiac damage by supporting or restoring heart function, is continuously improving. Common MTE strategies include an engineered ‘vehicle’, which may be a porous scaffold or a dense substrate or patch, made of either natural or synthetic polymeric materials. The function of the substrate is to aid transportation of cells into the diseased region of the heart and support their integration. This book, which contains chapters written by leading experts in MTE, gives a complete analysis of the area and presents the latest advances in the field. The chapters cover all relevant aspects of MTE strategies, including cell sources, specific TE techniques and biomaterials used. Many different cell types have been suggested for cell therapy in the framework of MTE, including autologous bone marrow-derived or cardiac progenitors, as well as embryonic or induced pluripotent stem cells, each having their particular advantages and disadvantages. The book also considers a complete range of biomaterials, examining different aspects of their application in MTE, such as biocompatibility with cardiac cells, mechanical capability and compatibility with the mechanical properties of the native myocardium as well as degradation behaviour in vivo and in vitro. Although a great deal of research is being carried out in the field, this book also addresses many questions that still remain unanswered and highlights those areas in which further research efforts are required. The book will also give an insight into clinical trials and possible novel cell sources for cell therapy in MTE.

Tissue engineering --- Cardiovascular system --- Culture Techniques --- Heart --- Myocardial Ischemia --- Muscles --- Investigative Techniques --- Muscle, Striated --- Analytical, Diagnostic and Therapeutic Techniques and Equipment --- Clinical Laboratory Techniques --- Heart Diseases --- Musculoskeletal System --- Vascular Diseases --- Cardiovascular System --- Cardiovascular Diseases --- Tissues --- Anatomy --- Diseases --- Tissue Engineering --- Myocardium --- Myocardial Infarction --- Methods --- Health & Biological Sciences --- Biomedical Engineering --- Treatment --- Myocardium. --- Tissue engineering. --- Cardiac muscle --- Heart muscle --- Muscle --- Engineering. --- Gene therapy. --- Cardiology. --- Stem cells. --- Biomedical engineering. --- Biomaterials. --- Biomedical Engineering. --- Stem Cells. --- Gene Therapy. --- Biomedical engineering --- Regenerative medicine --- Tissue culture --- Biomedical Engineering and Bioengineering. --- Therapy, Gene --- Genetic engineering --- Therapeutics --- Biocompatible materials --- Biomaterials --- Medical materials --- Medicine --- Materials --- Biocompatibility --- Prosthesis --- Colony-forming units (Cells) --- Mother cells --- Progenitor cells --- Cells --- Clinical engineering --- Medical engineering --- Bioengineering --- Biophysics --- Engineering --- Internal medicine --- Bioartificial materials --- Hemocompatible materials --- Biomaterials (Biomedical materials)

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