Caloric restriction improves endothelial dysfunction during vascular aging: Effects on nitric oxide synthase isoforms and oxidative stress in rat aorta.

Aging is characterized by activation of inducible over endothelial nitric oxide synthase (iNOS and eNOS), impaired antioxidant activity and increased oxidative stress, which reduces nitric oxide bioavailability and causes endothelial dysfunction. Caloric restriction (CR) blunts oxidative stress. We investigated whether CR impacts endothelial dysfunction in aging and the underlying mechanisms. Aortas from young (YC, 6 months of age) and old (OC, 24 months of age) rats ad-libitum fed and from old rats caloric-restricted for 3-weeks (OR, 26%) were investigated. Endothelium-dependent vasorelaxation was impaired in OC, associated with reduced eNOS and increased iNOS expression (P<0.05). Aortic nitrite was similar in OC and YC, but the contribution of calcium-independent NOS to total NOS activity was increased whereas that of calcium-dependent NOS was reduced (p≤0.0003). Plasma thiobarbituric acid-reactive substances (TBARS) were elevated in OC as well as aortic nitrotyrosine (P<0.05). Expression of manganese superoxide dismutase (MnSOD) and total SOD activity were impaired in OC (P<0.05 vs. YC), whereas copper-zinc (CuZn) SOD expression was similar in OC and YC. CR restored endothelial dysfunction in old rats, reduced iNOS expression, total nitrite and calcium-independent NOS activity in aorta (P<0.05) without changes in eNOS expression and calcium-dependent NOS activity. Sirtuin-1 expression did not differ among groups. Plasma TBARS and aortic nitrotyrosine were reduced (P<0.05) in OR compared with OC. In OR CuZnSOD protein and SOD activity increased (P<0.05) without changes in MnSOD expression. Short-term CR improves age-related endothelial dysfunction. Reversal of altered iNOS/eNOS ratio, reduced oxidative stress and increased SOD enzyme activity rather than enhanced NO production appear to be involved in this effect.

Zanetti M ，Gortan Cappellari G ，Burekovic I ，Barazzoni R ，Stebel M ，Guarnieri G ... -  《-》

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.

Gong X ，Ma Y ，Ruan Y ，Fu G ，Wu S ... -  《-》

Adiponectin improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity.

Li R ，Wang WQ ，Zhang H ，Yang X ，Fan Q ，Christopher TA ，Lopez BL ，Tao L ，Goldstein BJ ，Gao F ，Ma XL ... -  《AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM》

Nitric oxide dynamics and endothelial dysfunction in type II model of genetic diabetes.

Bitar MS ，Wahid S ，Mustafa S ，Al-Saleh E ，Dhaunsi GS ，Al-Mulla F ... -  《EUROPEAN JOURNAL OF PHARMACOLOGY》

Cyclooxygenase-2 inhibition improves vascular endothelial dysfunction in a rat model of endotoxic shock: role of inducible nitric-oxide synthase and oxidative stress.

Virdis A ，Colucci R ，Fornai M ，Blandizzi C ，Duranti E ，Pinto S ，Bernardini N ，Segnani C ，Antonioli L ，Taddei S ，Salvetti A ，Del Tacca M ... -  《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》