Dysfonction myocardique septique (un nouveau rôle pour les effecteurs de l'apoptose)

En dépit de l'amélioration des thérapeutiques anti-infectieuses, le choc infectieux ou septique s'accompagne d'une mortalité extrêmement élevée. Dans l'évolution de la maladie, l'apparition d'une dysfonction myocardique est un élément de mauvais pronostic. Celle-ci est habituellement attribuée aux effets délétères des différents médiateurs libérés lors de la réponse inflammatoire. Les processus d'apoptose sont également impliqués dans la physiopathologie de la dysfonction myocardique septique. Dans un premier temps, notre travail a consisté à caractériser in vivo et in vitro un modèle de défaillance myocardique septique. Le modèle in vivo a permis de vérifier l'intensité de la réponse inflammatoire systémique et myocardique par l'étude des voies d'activation cellulaire NFkB dépendantes. Le modèle in vitro a permis d'établir le lien fonctionnel entre l'activation du processus apoptotique induit par des molécules pro-apoptotiques telles que la sphingosine et l'apparition d'une anomalie contractile de la cellule cardiaque. Ces résultats nous ont conduits à démontrer par quels mécanismes le processus apoptotique pouvait altérer la fonction contractile. Nos travaux ont montré que les processus enzymatiques et mitochondriaux d'apoptose sont rapidement activés mais que l'activation des caspases effectrices, enzymes protéolytiques, ne conduit pas à la dégradation nucléaire terminale et à la mort cellulaire. En revanche, les caspases effectrices, à l'origine d'une désorganisation des sarcomères et d'une perturbation de l'homéostasie calcique, sont directement responsables de la défaillance cardiaque. Ainsi, les connaissances fondamentales acquises au cours de ce travail de thèse seront directement valorisables par la mise au point de nouvelles stratégies thérapeutiques du choc septique humain.Despite numerous advances in medical treatment, infectious shock also called septic shock is associated with an extremely high mortality rate. Sepsis-induced myocardial dysfunction is greatly associated with a fatal outcome. Most of the sepsis-induced myocardial dysfunction has been attributed to the deleterious effects of mediators released during the inflammatory response. Apoptosis processes are also involved in the pathogenesis of sepsis-induced myocardial dysfunction. The first aim of our study was to characterize both an in vivo and an in vivo model of sepsis-induced myocardial dysfunction. First, in the in vivo model, we checked that NFkB-dependent pathways, which represent a hallmark of the inflammatory response, were activated. In the in vitro model, the use of sphingosine, a pro-apoptotic molecule, unravelled a possible link between apoptotic pathway activation and cardiac cell contractile dysfunction. These results required further studies in order to explain how apoptotic processes may lead to myocardial dysfunction. We showed that mitochondria and apoptotic proteases are rapidly activated. Interestingly, although effector caspases are not associated with terminal nuclear degradation and cell death these proteolytical enzymes lead to sarcomeric destruction and calcium homeostasis alterations. Such modifications are responsible for contractile dysfunction Thus, these new fundamental mechanisms could be useful to develop new therapeutic strategies in the human septic shock.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Mitochondria and endoplasmic reticulum: Targets for a better insulin sensitivity in skeletal muscle?

International audienceObesity and its associated metabolic disorders represent a major health burden, with economic and social consequences. Although adapted lifestyle and bariatric surgery are effective in reducing body weight, obesity prevalence is still rising. Obese individuals often become insulin-resistant. Obesity impacts on insulin responsive organs, such as the liver, adipose tissue and skeletal muscle, and increases the risk of cardiovascular diseases, type 2 diabetes and cancer. In this review, we discuss the effects of obesity and insulin resistance on skeletal muscle, an important organ for the control of postprandial glucose. The roles of mitochondria and the endoplasmic reticulum in insulin signaling are highlighted and potential innovative research and treatment perspectives are proposed

Targeting Oxidative Stress and Mitochondrial Dysfunction in the Treatment of Impaired Wound Healing: A Systematic Review

Wound healing is a well-tuned biological process, which is achieved via consecutive and overlapping phases including hemostasis, inflammatory-related events, cell proliferation and tissue remodeling. Several factors can impair wound healing such as oxygenation defects, aging, and stress as well as deleterious health conditions such as infection, diabetes, alcohol overuse, smoking and impaired nutritional status. Growing evidence suggests that reactive oxygen species (ROS) are crucial regulators of several phases of healing processes. ROS are centrally involved in all wound healing processes as low concentrations of ROS generation are required for the fight against invading microorganisms and cell survival signaling. Excessive production of ROS or impaired ROS detoxification causes oxidative damage, which is the main cause of non-healing chronic wounds. In this context, experimental and clinical studies have revealed that antioxidant and anti-inflammatory strategies have proven beneficial in the non-healing state. Among available antioxidant strategies, treatments using mitochondrial-targeted antioxidants are of particular interest. Specifically, mitochondrial-targeted peptides such as elamipretide have the potential to mitigate mitochondrial dysfunction and aberrant inflammatory response through activation of nucleotide-binding oligomerization domain (NOD)-like family receptors, such as the pyrin domain containing 3 (NLRP3) inflammasome, nuclear factor-kappa B (NF-κB) signaling pathway inhibition, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)