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Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of Nrf2‐mediated antioxidant response
Author(s) -
Ungvari Zoltan,
BaileyDowns Lora,
Guatam Tripti,
Sonntag W.E.,
Csiszar Anna
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1093.10
Subject(s) - oxidative stress , gclc , homeostasis , medicine , reactive oxygen species , keap1 , oxidative phosphorylation , transcription factor , microbiology and biotechnology , endocrinology , downregulation and upregulation , antioxidant , biology , chemistry , gene , biochemistry
Aging increases vascular oxidative stress promoting cardiovascular diseases. Nrf2 is a transcription factor, which is activated by ROS in the vasculature of young animals leading to the up‐regulation of numerous antioxidant genes. We tested whether aging alters the homeostatic role of Nrf2‐driven free radical detoxification mechanisms. In the aorta of F344xBN rats age‐related progressive increase in O 2 − production was associated with a decreased nuclear Nrf2 activity and a down‐regulation of the Nrf2 target genes NQO1, GCLC and HMOX1. Aging also down‐regulates Nrf2 expression. In cultured aorta segments of young rats H 2 O 2 and high glucose significantly increased nuclear translocation of Nrf2 and up‐regulates the expression of Nrf2 target genes, whereas these responses were blunted in aged vessels. High glucose‐induced oxidative stress was exacerbated in aged aortas, as compared to responses obtained in young vessels. Aging also progressively increased vascular sensitivity to the pro‐apoptotic effects of H2O2 and high glucose treatments. Taken together, the results of this study suggest that adaptive activation of the Nrf2/ARE pathway confers protection against increased ROS production in young animals, whereas dysregulation of Nrf2 in aging promotes vascular oxidative stress and increases sensitivity of aged vessels to oxidative stress‐induced cellular damage.(Funding: ADA, AFAR, NIH)