Endothelial dysfunction and increased oxidative stress in mitochondrial diseases.

Mitochondrial diseases (MDs) are a clinically heterogeneous group of disorders characterized by impairment of the respiratory chain function with altered oxidative phosphorylation. We tested the hypothesis that the function of vascular endothelium is affected by increased oxidative stress in MDs. Twelve patients with MDs and pair-matched controls were studied. Endothelial function was assessed measuring flow-mediated vasodilatation (FMD) of brachial and common femoral arteries. The test was repeated after vitamin C (500 mg bid) and E (400 mg od) supplementation for 30 days and 90 days after vitamins withdrawal. FMD was reduced in patients compared to controls [mean±SEM; AUC/t brachial artery: 1.05±0.24\% vs. 4,19±0.59\%, P<0.001; femoral artery: 0.98±0.19\% vs. 2.36±0.29\%, P=0.001] and correlated (brachial artery) with plasma lactate (r= -0.63, P<0.01). Urinary 8-iso-PGF2α was higher in patients than controls [505.6±85.9 pg/mg creatinine vs. 302.5±38.7 pg/mg creatinine; P<0.05] and correlated with plasma lactate (r=0.70, P<0.05). Immunohistochemical analysis showed 8-iso-PGF2α staining in MD-affected striated muscle cells and in blood vessels in muscle biopsy of patients. Antioxidant vitamins transiently restored FMD in patients [brachial artery: [D AUC/τ= +1.38±0.49\%, P<0.05; femoral artery: +0.98±0.24\%, P<0.01] and had no effect on FMD in controls [brachial artery -1.3±0.63\% and common femoral artery -0.58±0.30\%], thus abolishing the differences between patients and controls. The present results indicate that oxidative stress is increased and is, at least partly, responsible for endothelial dysfunction in MDs.