Oxidative stress and endothelial dysfunction in pulmonary arteries of aged rats

Abstract

Aging in the systemic circulation is associated with generalized endothelial dysfunction and increased oxidative stress, which are thought to contribute to the increased morbidity and mortality of cardiovascular diseases in the elderly. Previous studies have shown that pulmonary artery pressure and vascular resistance increase with normal aging in humans, yet age-related functional and phenotypic changes in the pulmonary arteries have not been characterized. To determine whether in the pulmonary circulation aging elicits endothelial dysfunction and oxidative stress, isolated pulmonary arteries of young (3 mo old) and aged (28 mo old) F344 rats were compared. We found that aging in rat pulmonary arteries is associated with impaired acetylcholine-induced relaxation and vascular oxidative stress [assessed by dihydroethidine and 5 (and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate-acetyl ester fluorescence assays]. Endothelial dysfunction in the aged pulmonary vessels is reversed by the inhibition of NAD(P)H oxidase. The expressions of gp91(phox) (both mRNA and protein), NAD(P)H oxidase isoform type 1 (Nox-1; mRNA), and Nox-4 (mRNA) tend to increase in aged vessels; however, only changes in Nox-4 reached statistical significance. In pulmonary arteries of aged rats, the protein expression of endothelial nitric oxide synthase, Cu,Zn-SOD, Mn-SOD, and glutathione peroxidase is unaltered, whereas the expression of catalase is significantly decreased. Our results suggest that aging is associated with oxidative stress and endothelial dysfunction in the pulmonary arteries, which may contribute to the age-related functional alterations in the pulmonary circulation.

Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice

“…We observed significant reductions in endothelial function with aging in wild-type mice that were largely reversible with the NAD(P)H oxidase inhibitors apocynin or gp91ds-tat. This is consistent with previous work demonstrating that NAD(P)H oxidase (and Nox2-derived radicals in particular) are important contributors to age-related declines in endothelial function (10,20,33).…”

“…This reduced antioxidant capacity is consistent with data from previous reports in aging mice and may be in part due to age-associated reductions the transcription factors DJ-1 and members of the FOXO family, ultimately resulting in reductions in Nrf2 (8,38). NAD(P)H oxidase-derived ROS have also been shown to be increased with aging and to play a key role in limiting nitric oxide bioavailability (20,33) and promoting fibrosis in aged conduit vessels (17). When combined with age-related reductions in eNOS and SIRT1 expression, these molecular changes would be expected to strongly favor perivascular fibrosis and vascular stiffening with aging (16).…”

Resveratrol reduces vascular cell senescence through attenuation of oxidative stress by SIRT1/NADPH oxidase-dependent mechanisms

“…It has been shown that Res can reduce oxidative stress in vascular cells by decreasing the expression or the activity of NADPH oxidase [24,25]. A substantial number of studies in rodents reported that NADPH oxidase-mediated O 2 − production in arteries [26,27] is higher in aged rodents in comparison to that of younger animals, indicating that the expressions of NADPH oxidase tend to increase in aged blood vessels [28]. Given the aforementioned results, we suppose that Res can attenuate vascular cell aging through decreasing the NADPH oxidase expression.…”

The Aging Heart and Estrogen

“…This increase in IL-6 and TNF could be improved by treatment of the cells with E2. Strikingly, the aged ovx cardiac myocytes had a markedly reduced ability to handle reactive oxygen species (ROS), the production of which is known to increase with age [14]. E2 treatment of the cardiac myocytes was unable to reduce the ROS, even though it had a positive effect on cytokine levels.…”