{"record":{"leader":"cx  r22     2  45","datafield":[{"ind2":" ","ind1":" ","subfield":{"code":"a","content":"20171213afrey50      ba0"},"tag":100},{"ind2":" ","ind1":" ","subfield":[{"code":"a","content":"fre"},{"code":2,"content":"639-2"}],"tag":101},{"ind2":" ","ind1":" ","subfield":{"code":"a","content":2015},"tag":103},{"ind2":" ","ind1":" ","subfield":[{"code":"a","content":"k"},{"code":"f","content":"fre"}],"tag":104},{"ind2":" ","ind1":" ","subfield":[{"code":"a","content":0},{"code":"b","content":"#"},{"code":"c","content":"#"}],"tag":106},{"ind2":" ","ind1":" ","subfield":{"code":"a","content":"AFNOR"},"tag":152},{"ind2":" ","ind1":" ","subfield":{"code":"a","content":"Oeuvre Textuelle"},"tag":189},{"ind2":" ","ind1":" ","subfield":[{"code":7,"content":"ba0yba0"},{"code":"t","content":"Etude des voies de signalisation impliquées dans la phosphorylation des protéines du myofilament dans l'insuffisance cardiaque"}],"tag":241},{"ind2":" ","ind1":" ","subfield":[{"code":7,"content":"ba0yba0y"},{"code":"a","content":"Avec plus de 3,5 millions de nouveaux cas diagnostiqués chaque année, l\u2019insuffisance cardiaque (IC) touche actuellement plus de 15 millions d\u2019européens et représente ainsi la première cause de mortalité cardiovasculaire en Europe. Malgré les avancées de la recherche cardiovasculaire, l\u2019IC reste une maladie grave et de mauvais pronostic. En effet, plus de 50% des patients meurent dans les 5 années suivant le diagnostic. La compréhension des mécanismes physiopathologiques sous-jacents, encore largement inconnus, permettrait de développer des thérapeutiques visant à soigner les causes de l\u2019IC plutôt que les conséquences et ainsi d\u2019améliorer la prise en charge des patients. La contribution majeure des modifications post-traductionnelles (MPTs) dans la régulation de l\u2019expression génique, de l\u2019activité enzymatique ainsi que dans la régulation fonctionnelle des protéines font des MPTs les intégrateurs de l'adaptation dynamique du phénotype. C\u2019est pourquoi l\u2019équipe a réalisé des analyses phosphoprotéomiques dans un modèle expérimental d\u2019IC chez le rat à 2 mois post-infarctus du myocarde (IDM). Ces analyses ont permis de mettre en évidence d\u2019une augmentation du niveau de phosphorylation en sérine de la Desmine dans les ventricules gauches (VG) de rats IC par rapport aux témoins.Notre étude vise à identifier d\u2019une part les kinases impliquées dans la phosphorylation de la Desmine et d\u2019autre part à déterminer l\u2019impact de l\u2019augmentation de la forme phosphorylée de la Desmine sur son devenir dans le modèle in vivo.Par analyse bioinformatique, nous avons sélectionné les kinases potentiellement impliquées dans la phosphorylation de la Desmine. L\u2019étude de la régulation de ces kinases dans le modèle d\u2019IC chez le rat a permis de mettre en évidence la présence d\u2019une plus grande quantité d\u2019unités actives de PKC zeta et de GSK3 beta dans les VG de rats IC à 2 mois post-IDM. In vitro, l\u2019inhibition de PKC zeta entraîne à la fois une diminution de l\u2019activité GSK3 beta ainsi qu\u2019une modulation du profil de phosphorylation de la Desmine. L\u2019ensemble de ces données suggère l\u2019implication de PKC zeta et de GSK3 beta dans l\u2019augmentation du niveau de phosphorylation de la Desmine dans le modèle d\u2019IC chez le rat. Néanmoins, leur action directe sur la Desmine, en cascade ou encore indirecte via d\u2019autres partenaires reste encore à définir.Par immunofluorescence, nous avons mis en évidence la présence d'agrégats de Desmine dans les VG de rats IC à 2 mois post-IDM possiblement formés suite à son hyperphosphorylation. Nous avons émis l\u2019hypothèse que ces agrégats de Desmine, comme toute protéine agrégée, seraient toxiques pour le cardiomyocyte et nécessiteraient l'intervention des systèmes protéolytiques pour être éliminés afin d'assurer la survie cellulaire. L\u2019étude du système ubiquitine protéasome, de la macroautophagie et de l\u2019autophagie médiée par le chaperonnes (CMA) dans le modèle d\u2019IC chez le rat à 7 jours, 1 et 2 mois post-IDM suggère que l\u2019inefficacité de la macroautophagie à 7 jours post-IDM et la diminution de son activité au cours du temps entraînerait une accumulation cytosolique de Desmine phosphorylée mais également l\u2019induction de la CMA afin d\u2019assurer la clairance de cette dernière. In vitro, nous avons montré que l\u2019induction pharmacologique de la CMA entraîne une diminution du niveau de Desmine ainsi qu\u2019une modulation de son profil de phosphorylation.L\u2019augmentation de phosphorylation en sérine de la Desmine dans les VG de rats IC à 2 mois, dépendante de la PKC zeta et/ou GSK3 beta, semble entraîner l\u2019accumulation cytosolique de Desmine ainsi que la formation d\u2019agrégats dans les VG de rat IC qui pourraient participer à la dysfonction contractile observée au cours de l\u2019IC. En réponse à l'inefficacité de la macroautophagie, la CMA serait activée afin d\u2019assurer l\u2019élimination de la Desmine phosphorylée et ainsi la survie du cardiomyocyte au cours de l\u2019IC."}],"tag":300},{"ind2":" ","ind1":" ","subfield":[{"code":7,"content":"ba0yba0y"},{"code":"a","content":"With over 3,5 million new cases each year, heart failure (HF) currently affects more than 15 million of European individuals and thus represents the leading cause of cardiovascular mortality in Europe. Despite advances in cardiovascular research, HF remains a serious disease with poor prognosis. Indeed, more than 50 per cent of patients die within 5 years after diagnosis. Understanding the underlying physiopathological mechanisms would allow the development of therapeutics to treat the causes of HF rather than the consequences of the disease, thereby improving the medical care of patients. The major contribution of post-translational modifications (PTMs) in the regulation of gene expression, enzyme activity as well as in the functional regulation of proteins, turns PTMs into integrators of the dynamic adaptation of the phenotype. For this reason, the team performed phosphoproteomic analyses in an experimental rat model of HF at 2 monhs following myocardial infarction (MI). These analyses revealed an increase of the phosphorylation levels of Desmin at serine residues in left ventricles (LV) of HF rats compared to sham rats.The aim of our study is to identify the kinases which are implicated in Desmin phosphorylation on one hand, and the impact and behavior of increased phosphorylated Desmin in cardiomyocyte on the other hand.By bioinformatic analysis, we first selected the kinases which are potentially implicated in Desmin phosphorylation. Then, we studied the enzymatic regulation of selected kinases in an experimental rat model of HF, which allowed the identification of active PKC zeta and GSK3 beta in the LV of HF rats at 2 months. In vitro, pharmacological inhibition of PKC zeta leads to a decreased of GSK3 beta activity as well as a modulation of the phosphorylated Desmin profiles. Taken together, these data suggest an implication of PKC zeta and GSK3 beta in the increase of Desmin phosphorylation levels in the LV of HF rats. However, their direct, consecutive or indirect implication on Desmin phosphorylation remains to be evaluated.By immunofluorescence, we observed the presence of aggregated Desmin in LV of HF rats at 2 months post-MI that suggest that these could be the result of Desmin hyperphosphorylation. We hypothesized that these Desmin aggregates, like other aggregated proteins, could be toxic for cardiomyocytes and need to be cleared by proteolytic systems to ensure cell survival.The study of proteolytic systems in the in vivo model showed that while the UPS is not modulated all along LV remodeling, macroautophagy decreases with time and could thus drive cytosolic accumulation of phosphorylated Desmin in LV of HF rats. At the same time, CMA seems to be activated thereby ensure phosphorylated Desmin clearance. In vitro, we have shown that pharmacological induction of CMA results in lower phosphorylated Desmin levels.In conclusion, increased Desmin phosphorylation levels seems to be dependent of PKC zeta and/or GSK3 beta activation in LV of HF rats at 2 months after MI. This elevation could drive the cytosolic accumulation and aggregation of Desmin, which could be involved in the contractile dysfunction observed during HF. Finally, as a result of decreased macroautophagy, CMA could be activated in LV of HF rats to ensure phosphorylated Desmin clearance and thus cardiomyocyte survival."}],"tag":300},{"ind2":0,"ind1":" ","subfield":[{"code":"b","content":"Thèse de doctorat"},{"code":"c","content":"Sciences de la vie et de la santé"},{"code":"e","content":"Lille 2"},{"code":"d","content":2015}],"tag":328},{"ind2":" ","ind1":" ","subfield":[{"code":7,"content":"ba0yba0"},{"code":"t","content":"Study of signaling pathways involved in the phosphorylation of proteins of the myofilament heart failure"}],"tag":441},{"ind2":1,"ind1":" ","subfield":[{"code":3,"content":221433961},{"code":7,"content":"ba0yba02"},{"code":"a","content":"Bouvet"},{"code":"b","content":"Marion"},{"code":"f","content":"1989-...."},{"code":4,"content":"070"}],"tag":501},{"ind2":1,"ind1":" ","subfield":[{"code":3,"content":"079539122"},{"code":7,"content":"ba0yba02"},{"code":"a","content":"Lamblin"},{"code":"b","content":"Nicolas"},{"code":"f","content":"1969-...."},{"code":4,"content":727}],"tag":501},{"ind2":2,"ind1":0,"subfield":[{"code":3,"content":"026404389"},{"code":7,"content":"ba0yba02"},{"code":"a","content":"Université du droit et de la santé"},{"code":"c","content":"Lille"},{"code":"c","content":"1969-2017"},{"code":4,"content":295}],"tag":511},{"ind2":2,"ind1":0,"subfield":[{"code":3,"content":147705126},{"code":7,"content":"ba0yba02"},{"code":"a","content":"École graduée Biologie-Santé"},{"code":"c","content":"Lille"},{"code":"c","content":"2000-...."},{"code":4,"content":996}],"tag":511},{"ind2":2,"ind1":0,"subfield":[{"code":3,"content":193516136},{"code":7,"content":"ba0yba02"},{"code":"a","content":"Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement"},{"code":"c","content":"Lille"},{"code":4,"content":981}],"tag":511},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":"027366278"},{"code":"a","content":"Insuffisance cardiaque"},{"code":2,"content":"rameau"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":168661969},{"code":"a","content":"Remodelage ventriculaire"},{"code":2,"content":"rameau"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":180486330},{"code":"a","content":"Autophagie"},{"code":2,"content":"rameau"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":"029540089"},{"code":"a","content":"Phosphorylation"},{"code":2,"content":"rameau"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":"034111964"},{"code":"a","content":"Molécules chaperonnes"},{"code":2,"content":"rameau"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":"040716252"},{"code":"a","content":"Défaillance cardiaque"},{"code":3,"content":"040839486"},{"code":"x","content":"Dissertation universitaire"},{"code":2,"content":"fmesh"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":"04084532X"},{"code":"a","content":"Remodelage ventriculaire"},{"code":3,"content":"040839486"},{"code":"x","content":"Dissertation universitaire"},{"code":2,"content":"fmesh"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":"04066760X"},{"code":"a","content":"Autophagie"},{"code":3,"content":"040839486"},{"code":"x","content":"Dissertation universitaire"},{"code":2,"content":"fmesh"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":"04075961X"},{"code":"a","content":"Phosphorylation"},{"code":3,"content":"040839486"},{"code":"x","content":"Dissertation universitaire"},{"code":2,"content":"fmesh"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":"040692469"},{"code":"a","content":"Desmine"},{"code":3,"content":"040839486"},{"code":"x","content":"Dissertation universitaire"},{"code":2,"content":"fmesh"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":3,"content":"04071652X"},{"code":"a","content":"Protéines du choc thermique"},{"code":3,"content":"040839486"},{"code":"x","content":"Dissertation universitaire"},{"code":2,"content":"fmesh"}],"tag":606},{"ind2":" ","ind1":" ","subfield":[{"code":7,"content":"ba0yba0"},{"code":3,"content":"027253139"},{"code":"a","content":"Thèses et écrits académiques"},{"code":2,"content":"rameau"}],"tag":608},{"ind2":" ","ind1":0,"subfield":{"code":"a","content":"Protéo-toxicité"},"tag":610},{"ind2":" ","ind1":" ","subfield":[{"code":"a","content":610},{"code":2,"content":"TEF"}],"tag":686},{"ind2":3,"ind1":" ","subfield":[{"code":"a","content":"FR"},{"code":"b","content":"Abes"},{"code":"c","content":20260402},{"code":"g","content":"AFNOR"}],"tag":801}],"controlfield":[{"tag":"001","content":221506934},{"tag":"003","content":"http://www.idref.fr/221506934"},{"tag":"004","content":20171213},{"tag":"005","content":20260402015233},{"tag":"006","content":"0499"},{"tag":"007","content":"0499"},{"tag":"008","content":"Tr2"}]}}