Facteurs environnementaux et génétiques pouvant influencer l'apparition de la rigidité artérielle (étude du rat Zucker et de la souris Klotho)

Les conséquences cardiovasculaires du vieillissement sont l'une des principales causes de mortalité. En plus de l'âge chronologique, plusieurs autres facteurs peuvent influencer l'apparition des modifications liées au vieillissement. L'étude des déterminants génétiques et environnementaux accélérateurs du vieillissement cardiovasculaire pourrait améliorer la prévention de ces pathologies. Nous avons démontré chez le rat Zucker (modèle de syndrome métabolique) en fin de vie (80 semaines) que l'obésité et les troubles métaboliques associés et le vieillissement agissent de façon synergique pour modifier la structure et la fonction vasculaire, en ciblant les propriétés endothéliales. L'augmentation précoce des acides gras libres (AGL) plasmatiques et les altérations de réactivité carotidienne qu'ils induisent sont des mécanismes clés du développement de la rigidité artérielle dans ce modèle. La souris déficiente pour le gène Klotho (Kl) possède une faible espérance de vie, un vieillissement accéléré et des pathologies semblables à celles de l'homme âgé. Nous avons caractérisé le phénotype artériel (peu connu) des souris Kl+/- à 6 et 12 mois, en comparaison de leurs contrôles Kl+/+ aux mêmes âges. Nous avons démontré dans ce modèle que dans des conditions basales, les souris Kl+/- ne présentent pas de phénotype de vieillissement accéléré de la paroi artérielle à l'âge de 12 mois. Néanmoins, à l'âge de 6 mois, les souris Kl+/- présentent une augmentation de leur rigidité carotidienne, en faveur d'une altération de la fonction vasculaire. L'étude de ces deux modèles nous a ainsi permis d'évaluer l'implication de l'obésité et de la protéine Klotho dans le vieillissement artérielThe cardiovascular consequences of aging are a leading cause of death. In addition to chronological age, several other factors may influence the onset of changes associated with aging. The study of genetic and environmental determinants of cardiovascular aging accelerators could improve prevention of these diseases. We have demonstrated in very old (80 weeks) Zucker rats (model of metabolic syndrome) that obesity and associated metabolic disorders act synergistically with aging to alter the vascular structure and function by targeting endothelial properties. The early increase in plasma free fatty acids (FFA) and alterations in carotid responsiveness induced by AGL are key mechanisms of development of arterial stiffness in this model. Mouse deficient for the gene Klotho (Kl) has a short life expectancy, accelerated aging and diseases similar to an old man. We characterized the arterial phenotype (unknown) mice Kl +/- at 6 and 12 months, compared to their controls K +/+ at the same ages. We have demonstrated in this model that in basal conditions, Kl +/- mice show no phenotype of an accelerated aging of the arterial wall at the age of 12 months. However, at the age of 6 months, mice Kl +/- show an increase in carotid stiffness in favor of an alteration of vascular function. The study of these two models has allowed us to assess the implication of obesity and Klotho protein in aging arteriesNANCY1-Bib. numérique (543959902) / SudocSudocFranceF

White blood cells telomere length is shorter in males with type 2 diabetes and microalbuminuria

OBJECTIVE - To examine differences in telomere (terminal restriction fragment [TRF]) length and pulse wave velocity (PWV) - an index of arterial stiffness-in patients with type 2 diabetes with and without microalbuminuria (MA). RESEARCH DESIGN AND METHODS - A total of 84 men with type 2 diabetes, 40 with MA and 44 without MA (aged 63.5 +/- 9.0 vs. 61.2 +/- 9.8 years), were studied. TRF length was determined in white blood cells. MA was defined as albumin excretion rate (AER) in the range of 30-300 mg/24 h in at least two of three 24-h urine collections. PWV was assessed using applanation tonometry. Markers of oxidative stress were also measured. RESULTS - TRF length was shorter in patients with MA than in those without MA (6.64 +/- 0.74 vs. 7.23 +/- 1.01 kb, respectively, P = 0.004). PWV was significantly higher in the patients with MA. Multivariate linear regression analysis in the total sample demonstrated an independent association between TRF length and age (P = 0.02), MA status (P = 0.04) or AER (P = 0.002), and plasma nitrotyrosine levels (P = 0.02). AER was associated significantly with PWV (P < 0.01). CONCLUSIONS - Subjects with type 2 diabetes and MA have shorter TRF length and increased arterial stiffness than those without MA. Additionally, TRF length is associated with age, AER, and nitrosative stress. As shorter TRF length indicates older biological age, the increased arterial stiffness in patients with type 2 diabetes who have MA may be due to the more pronounced “aging” of these subjects

Immune constitution monitoring after PBMC transplantation in complete DiGeorge syndrome: an eight-year follow-up.

International audienceA young boy with a confirmed complete DiGeorge Syndrome (cDGS) underwent a peripheral blood mononuclear cell transplantation (PBMCT) from his HLA-identical sister at 4.5 years of age, without a conditioning regimen. Eight years later, he is healthy with good immunological functions in the presence of a stable mixed T-cell chimerism. Absence of recent thymic emigrants is confirmed. We observe an inverted CD4+/CD8+ ratio, related to the CD8 subset expansion, a skewing of the TCR repertoire, especially on the CD8+ subset and a telomere loss on the CD8+ cells compared to the donor. However, these anomalies do not seem to have an impact on functional immunity. PBMCT in cDGS using an HLA-matched sibling donor provides good long-lasting immunity and is an easy alternative to bone marrow transplantation and to thymic transplantation