Papel de la insulina en la activación de la nadph oxidasaimplicación en la fisiopatología del síndrome metabólico

Résumé

ROLE OF INSULIN IN THE ACTIVATION OF THE NADPH OXIDASE. INVOLVEMENT IN THE PATHOPHYSIOLOGY OF THE METABOLIC SYNDROME. Julen Bidegain Aizpun, Centre for Applied Medical Research, Faculty of Pharmacy, University of Navarra, 2009. Insulin resistance (IR) is the main phenotypic characteristic in patients with metabolic syndrome (MetS). Oxidative stress plays a critic role in the development of this pathology, where NADPH oxidase is the most important source of superoxide anion. The objective of this work was to analyze whether the IR was able to modulate the oxidative stress in patients classified with MetS. NADPH oxidase-dependent ¿O2- production was determinated by luminescence in peripheral mononuclear cells from 125 patients with MetS (with 3 or more inclusion criterias of the NHLBI-2005). IR was defined using the homeostasis model assesment (HOMA-IR) index. Protein expression of the different subunits of NADPH oxidase was determinated by Western blot. Several in vitro studies were carried out in a murine macrophagic line (RAW 264.7). The group of patients with IR showed higher risk of cardiovascular disease, defined by PROCAM index. Besides, this group of patients showed high levels of MMP-9, an independent marker of atherothrombosis, as well as a higher NADPH oxidase activity in comparison with the group of patients without IR. In agreement with this, the patients with IR showed a higher expression of p22phox protein, an essential subunity of NADPH oxidase, than insulin sensitive patients. These results suggest the association between p22phox levels and the NADPH oxidase activation. On the other hand, in RAW 264.7 cells insulin (100nM) stimulated the expression of p22phox in time-dependent manner. Besides, in experiments with the reporter gene of the luciferase, insulin stimulated the p22phox promoter transcriptional activity. In summary, the patients with IR show a higher cardiovascular disease risk, which is associated with the NADPH oxidase activation.