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Biomarqueurs pronostiques et cibles thérapeutiques du remodelage ventriculaire post infarctus du myocarde

Abstract : Heart failure following myocardial infarction is a complex pathology that occurs as a result of left ventricular remodeling. Left ventricular remodeling is mediated in part by extracellular cardiac matrix turnover and inflammation. Matrix metalloproteinase 9 (MMP9) and innate immune receptor Toll-like 4 (TLR4) are key mediators of left ventricular remodeling. Cardioprotective and anti-inflammatory nucleoside adenosine acts on left ventricular remodeling through still poorly characterized mechanisms. We hypothesized that adenosine regulates left ventricular remodeling through modulation of MMP9 and TLR4 pathways in macrophages. Using human primary macrophages, we showed that adenosine increases MMP9 production through the A3 receptor. In a second set of experiments, we observed that adenosine dampens inflammation through decreased cell-surface expression of TLR4. This effect, which inhibits pro-inflammatory cytokines production, is induced by adenosine A2A receptor. All together, these results contribute to a better understanding of the mechanisms underlying left ventricular remodeling and suggest a potential therapeutic use of adenosine. Our data suggest testing a therapeutic strategy with different adenosine analogs to prevent or limit left ventricular remodeling. Prediction of left ventricular remodeling after myocardial infarction is clinically relevant and would benefit from the discovery of new biomarkers. Proteomic analysis of plasma samples from a test cohort of 30 myocardial infarction patients identified haptoglobin as a potential prognostic biomarker. Human haptoglobin has 3 distinct isoforms: [alpha]1-[alpha]1, [alpha]2-[alpha]1 and [alpha]2-[alpha]2. Our results suggest that the presence of [alpha]2 isoform, together with low plasma levels of total haptoglobin, is associated with the development of heart failure. This proof-of-concept study suggested that haptoglobin could be added to the panel of existing biomarkers of heart failure
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Submitted on : Thursday, March 29, 2018 - 10:29:21 AM
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  • HAL Id : tel-01746260, version 1



Benjamin Haas. Biomarqueurs pronostiques et cibles thérapeutiques du remodelage ventriculaire post infarctus du myocarde. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2011. Français. ⟨NNT : 2011NAN10084⟩. ⟨tel-01746260⟩



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