59 research outputs found

    Statistical Modelling of Cardiovascular Data. An Introduction to Linear Mixed Models

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    Most of statistical approaches in cardiovascular research were based on variance analysis (ANOVA). However, most of the time, the assumption that data are independent is violated since several measures are performed on the same subject (repeated measures). In addition, the presence of intra- and inter-observers variability can potentially obscure significant differences. The linear mixed model (LMM) is an extended multivariate linear regression method of analysis that accounts for both fixed and random effects. LMM allows for addressing incomplete design cases. In this paper, LMM was applied to two sets of cardiovascular research data and compared to ANOVA. The first example is an analysis of heart rate in mice after atropine and propranolol injections. LMM shows an important mouse random effects that depends on pharmacological treatment and provides with accurate estimates for each significant experimental factors. When randomly suppressing observations from the data sets (20-30%) the time factor of Anova model becomes non significant while LMM still remains significant. The second example is the analysis of isolated coronary-perfused pressure of transgenic mice hearts. LMM evidenced a significant transgenic effect in both male and female animals, while, with ANOVA, the transgenic effects was limited to male mice only. In both cases, as compared to ANOVA, the LMM separately accounts for fixed and random effects, allowing thus for studying more adequately incomplete designs on repeated measures

    The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORγt and Controls Metabolic Disease

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    SummaryA high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease

    Homéostasie des espÚces oxygénées réactives et physiopathologie de l'hypertrophie/insuffisance cardiaque (focus sur l'isoforme Nox4 de la NADPH oxydase)

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    L'insuffisance cardiaque est un risque majeur de morbidité et de mortalité dans les pays industrialisés et constitue un problÚme majeur de santé publique. Ce syndrome est la voie finale de nombreuses maladies cardiaques qui induisent dans un premier temps un remodelage adaptatif du myocarde, l'hypertrophie du ventricule gauche. Il est de plus en plus évident que les espÚces oxygénées réactives interviennent dans le développement de l'hypertrophie et de l'insuffisance cardiaque, en impactant sur des voies moléculaires essentielles à la régulation du trophisme des cellules cardiaques ou à leur survie. Le systÚme NADPH Oxidase dédié à la production de ROS, source majoritaire dans le systÚme cardiovasculaire, est particuliÚrement impliqué dans le processus physiopathologique cardiaque. Nous avons confirmé que l'activité NADPH Oxidase est augmentée par des stress pro-trophiques, tant in vitro qu'in vivo, et que cette augmentation potentialise le développement de l'hypertrophie et de la défaillance cardiaque. Nous avons constaté les effets antioxydants d'un concentré du contenu en polyphénols de vin rouge, le Provinols tm, grùce auxquels nous supposons qu'il provoque l'adaptation bénéfique du coeur, en réponse à la surcharge chronique de pression, dans un modÚle de sténose aortique (TAC), chez le rat. L'isoforme Nox4 est majoritairement sollicité par une stimulation pro-trophique, in vitro. L'utilisation de son inhibiteur pharmacologique sélectif, le GKT137831, ne nous a pas permis de faire la démonstration du rÎle joué par l'augmentation de son activité de production de ROs, in vivo, dans le modÚle chirurgical de TAC, chez le rat ou la souris. Nous restons, à ce jour, dans l'impossibilité de conclure, quant à son rÎle délétÚre ou protecteur, au cours du remodelage morphologique et fonctionnel cardiaque, grùce à cet outil pharmacologique.Left Ventricular Hypertrophy (LVH) and most importantly heart failure are major causes of morbidity and mortality worldwide. Reactive Oxygen Species (ROS) such as anion superoxide (O2-) and H2O2 play an important role in regulating growth and death of cardiac myocytes and the hypertrophic process is mediated, in part, by oxidative stress-modulated signaling pathways. NADPH Oxidases (Nox) isoforms are a major source of ROS and play an important role in cardiovascular pathophysiology. Here, we demonstrate that NADPH Oxidase activity is augmented by hypertrophic stimuli, in vitro and in vivo. The latter is characterized by an increased Nox-dependent ROS production that may potentiate the development of LVH and its progression towards heart failure. Indeed, we suppose that a daily oral administration of Provinols tm, a mix of red wine polyphenols compounds, by limitating ROS production from NADPH Oxidase system, maintains an adaptative LVH and prevents cardiac dysfunction, in a model of pressure- overload induced by Thoracic Aortic Constriction (TAC) in rats. NADPH Oxidase 4 (Nox4) protein is overexpressed and produce more ROS in neonatal cardiomyocytes stimulated by PE, in vitro. Thus, its overactivation significantly enhanced PE-induced hypertrophy in cardiomyocytes, as evaluated by protein neosynthesis and cell area analysis. We have validated the effect of a new pharmacological selective inhibitor of Nox4 activity, GKT137831, on cultured cardiomyocytes. We have also investigated the impact of a daily oral administration of GKT137831 on cardiac remodeling and dysfunction occurred following TAC, in rats and further in mice. However, further investigation is still needed to understand whether Nox4 is beneficial or detrimental for myocardial adaptation to a chronic mechanical stress.PARIS7-BibliothÚque centrale (751132105) / SudocSudocFranceF

    Neuronal NO synthase mediates plenylephrine induced cardiomyocyte hypertrophy through facilitation of NFAT-dependent transcriptional activity

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    Neuronal nitric oxide synthase (NOS1) has been consistently shown to be the predominant isoform of NOS and/or NOS-derived NO that may be involved in the myocardial remodeling including cardiac hypertrophy. However, the direct functional contribution of NOS1 in this process remains to be elucidated. Therefore, in the present study, we attempted to use silent RNA and adenovirus mediated silencing or overexpression to investigate the role of NOS1 and the associated molecular signaling mechanisms during OKphenylephrine (PE)-induced cardiac hypertrophy growth in neonatal rat ventricular cardiomyocytes (NRVMs). We found that the expression of NOS1 was enhanced in PE-induced hypertrophic cardiomyocytes. Moreover, LVNIO treatment, a selective NOS1 inhibitor, significantly decreased PE-induced NRVMs hypertrophy and [3H]-leucine incorporation. We demonstrated that NOS1 gene silencing attenuated both the increased size and the transcriptional activity of the hypertrophic marker atrial natriuretic factor (ANF) induced by PE stimulation. Further investigation suggested that deficiency of NOS1-induced diminished NRVMS hypertrophy resulted in decreased calcineurin protein expression and activity (assessed by measuring the transcriptional activity of NFAT) and, an increased activity of the anti-hypertrophic pathway, GSK-3ÎČ (estimated by its augmented phosphorylated level). In contrast, exposing the NOS1 overexpressed NRVMs to PE-treatment further increased the hypertrophic growth, ANF transcriptional activity and calcineurin activity. Together, the results of the present study suggest that NOS1 is directly involved in controlling the development of cardiomyocyte hypertrophy. Keywords: Neuronal NO synthase, Cardiomyocyte hypertrophy, Gene silencing, Adenovirus, NFA
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