title: Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta.
abstract: Aging promotes oxidative stress in vascular endothelial and smooth muscle cells, which contribute to the development of cardiovascular diseases. NF-E2-related factor 2 (Nrf2) is a transcription factor, which is activated by reactive oxygen species in the vasculature of young animals, leading to adaptive upregulation of numerous reactive oxygen species detoxifying and antioxidant genes. The present study was designed to elucidate age-associated changes in the homeostatic role of Nrf2-driven free radical detoxification mechanisms in the vasculature of nonhuman primates. We found that carotid arteries of aged rhesus macaques (Macaca mulatta, age: ≥20 years) exhibit significant oxidative stress (as indicated by the increased 8-iso-PGF2α and 4-HNE content and decreased glutathione and ascorbate levels) as compared with vessels of young macaques (age:~10 years) that is associated with activation of the redox-sensitive proinflammatory transcription factor, nuclear factor-kappaB. However, age-related oxidative stress does not activate Nrf2 and does not induce Nrf2 target genes (NQO1, GCLC, and HMOX1). In cultured vascular smooth muscle cells (VSMCs) derived from young M mulatta, treatment with H(2)O(2) and high glucose significantly increases transcriptional activity of Nrf2 and upregulates the expression of Nrf2 target genes. In contrast, in cultured vascular smooth muscle cells cells derived from aged macaques, H(2)O(2)- and high glucose-induced Nrf2 activity and Nrf2-driven gene expression are blunted. High glucose-induced H(2)O(2) production was significantly increased in aged vascular smooth muscle cells compared with that in vascular smooth muscle cells from young M mulatta. Taken together, aging is associated with Nrf2 dysfunction in M mulatta arteries, which likely exacerbates age-related cellular oxidative stress, promoting nuclear factor-kappaB activation and vascular inflammation in aging.
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 N. E. 10th Street, Oklahoma City, OK 73104, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.forename: Lora
authors.initials: L
authors.lastname: Bailey-Downs
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.forename: Mingyi
authors.initials: M
authors.lastname: Wang
authors.forename: Robert E
authors.initials: RE
authors.lastname: Monticone
authors.forename: Richard
authors.initials: R
authors.lastname: Telljohann
authors.forename: John T
authors.initials: JT
authors.lastname: Pinto
authors.forename: Raphael
authors.initials: R
authors.lastname: de Cabo
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002339:Carotid Arteries / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000008:administration & dosage; D008253:Macaca mulatta / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D016877:Oxidants / Q000008:administration & dosage; D018384:Oxidative Stress; D046509:Tissue Culture Techniques; D014158:Transcription, Genetic / Q000187:drug effects; D014657:Vasculitis / Q000209:etiology
chemical_list: D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D016877:Oxidants; D006861:Hydrogen Peroxide