Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-kB activation in the nonhuman primate macaca mulatta

Zoltan Ungvari, Lora Bailey-Downs, Tripti Gautam, Danuta Sosnowska, Mingyi Wang, Robert E. Monticone, Richard Telljohann, John T. Pinto, Raphael De Cabo, William E. Sonntag, Edward Lakatta, Anna Csiszar

Research output: Contribution to journalArticle

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 2O 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 2O 2- and high glucose-induced Nrf2 activity and Nrf2-driven gene expression are blunted. High glucose-induced H 2O 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.

Original languageEnglish (US)
Pages (from-to)866-875
Number of pages10
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume66 A
Issue number8
DOIs
StatePublished - Aug 2011
Externally publishedYes

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NF-E2-Related Factor 2
NF-kappa B
Macaca mulatta
Primates
Blood Vessels
Oxidative Stress
Vascular Smooth Muscle
Smooth Muscle Myocytes
Macaca
Glucose
Reactive Oxygen Species
Transcription Factors
Up-Regulation
Genes
Dinoprost
Carotid Arteries
Oxidation-Reduction
Free Radicals
Glutathione
Cardiovascular Diseases

Keywords

  • Artery
  • Inflammation
  • Oxidative stress
  • Smooth muscle
  • Vascular aging

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology
  • Medicine(all)

Cite this

Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-kB activation in the nonhuman primate macaca mulatta. / Ungvari, Zoltan; Bailey-Downs, Lora; Gautam, Tripti; Sosnowska, Danuta; Wang, Mingyi; Monticone, Robert E.; Telljohann, Richard; Pinto, John T.; De Cabo, Raphael; Sonntag, William E.; Lakatta, Edward; Csiszar, Anna.

In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences, Vol. 66 A, No. 8, 08.2011, p. 866-875.

Research output: Contribution to journalArticle

Ungvari, Z, Bailey-Downs, L, Gautam, T, Sosnowska, D, Wang, M, Monticone, RE, Telljohann, R, Pinto, JT, De Cabo, R, Sonntag, WE, Lakatta, E & Csiszar, A 2011, 'Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-kB activation in the nonhuman primate macaca mulatta', Journals of Gerontology - Series A Biological Sciences and Medical Sciences, vol. 66 A, no. 8, pp. 866-875. https://doi.org/10.1093/gerona/glr092
Ungvari, Zoltan ; Bailey-Downs, Lora ; Gautam, Tripti ; Sosnowska, Danuta ; Wang, Mingyi ; Monticone, Robert E. ; Telljohann, Richard ; Pinto, John T. ; De Cabo, Raphael ; Sonntag, William E. ; Lakatta, Edward ; Csiszar, Anna. / Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-kB activation in the nonhuman primate macaca mulatta. In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2011 ; Vol. 66 A, No. 8. pp. 866-875.
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