Long-term atorvastatin improves age-related endothelial dysfunction by ameliorating oxidative stress and normalizing eNOS/iNOS imbalance in rat aorta

Vascular aging is characterized by vascular cell senescence, increased oxidative stress, and endothelial and inducible nitric oxide (NO) synthase (eNOS/iNOS) imbalance, which reduces NO bioavailability and causes endothelial dysfunction. We investigated whether long-term administration of atorvastatin affects endothelial dysfunction and the underlying mechanisms. Aortas from young (2 months), middle-aged (12 months), and old (20 months) control rats that had received a routine diet and from old rats (20 months) that had received a diet mixed with atorvastatin (5 mg/kg/day) for 8 months were investigated. Senescent phenotype, vascular reactivity, superoxide dismutase (SOD), malonyldialdehyde (MDA), total NO, calcium-dependent and -independent NOS activity, and eNOS, iNOS, and sirtuin-1 (SIRT1) expression at the transcriptional and translational levels were assessed in rat aortas. Comparisons between young, middle, and old control rats showed that the senescent phenotype was enhanced in intima and media (p < 0.01), and that MDA, calcium-independent NOS activity, and iNOS increased with age (p < 0.01), whereas endothelium-dependent relaxation, SOD, NO, calcium-dependent NOS activity, eNOS, the eNOS/iNOS ratio, and SIRT1 declined with age (p < 0.01). Compared with old controls, long-term administration of atorvastatin to old rats inhibited the senescent phenotype (p < 0.05), improved endothelium-dependent relaxation (p < 0.05 or 0.01), decreased MDA (p < 0.01), increased SOD, NO, eNOS, and SIRT1 expression (p < 0.01), and inhibited iNOS expression (not detectable) in aged rat aortas. The results indicate that the long-term administration of atorvastatin improves age-related endothelial dysfunction in aged rats via inhibition of the senescent phenotype, amelioration of oxidative stress, and normalization of eNOS/iNOS imbalance. (C) 2014 Elsevier Inc. All rights reserved.