Résumé :
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Mitochondrial diseases (MD) are multisystemic disorders, mostly affecting central nervous system, skeletal and cardiac muscle. To evaluate the hypothesis that in MD the vessel wall, in particular the vascular endothelium, may be affected by increased oxidative stress causing a reduction in nitric oxide (NO) availability, muscle biopsy specimens from sixteen patients with MD and different phenotypes have been studied. We tested the pathobiology of vasculature in MD by assaying the presence of 3-nitrotyrosine in muscle biopsies followed by the proteomic identification of proteins that undergo tyrosine nitration. We then studied the expression and the activity of nitric oxide synthase (NOS) enzymes that are responsible for the production of NO. 3-nitrotyrosine was specifically located in the small vessels of muscle tissue and the staining was stronger and evident in a much higher percentage of vessels from MD patients compared to age-matched controls. We then identified 11 specific proteins that are nitrated under pathological conditions and that are mainly involved in energy metabolism and located in mitochondria. In MD muscle biopsies we observed at protein level an up-regulation of endothelial NOS (eNOS) which is specifically located in the vascular endothelium, while no significant difference was present for neuronal NOS and inducible NOS. Total NOS activity, iducible NOS activity as well as activity of constitutive isoforms of NOS (eNOS and neuronal NOS) was increased in patients’ muscle biopsies compared to control muscles although the difference was not statistically significant. The present results provide evidence that vessel walls are a target of oxidative/nitrative stress in patients affected with mitochondrial respiratory chain dysfunction.
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