Age‐associated vascular oxidative stress, Nrf2 dysfunction and NF‐κB activation in the non‐human primate Macaca mulatta

Aging promotes oxidative stress in vascular endothelial and smooth muscle cells contributing to the development of cardiovascular diseases. Nrf2, a transcription factor, is activated by reactive oxygen species (ROS) in the vasculature of young animals, leading to up‐regulation of ROS detoxifying and antioxidant genes. The present study was designed to elucidate age‐associated changes of Nrf2‐driven free radical detoxification mechanisms in the vasculature of non‐human primates. We found that carotid arteries of aged rhesus macaques (~20 yrs) exhibit significant oxidative stress (as indicated by the increased 8‐iso‐PGF2α and 4‐HNE content and decreased GSH and ascorbate levels) as compared young macaques vessels (age: ~10 y). Although NF‐κB is activated, age‐related oxidative stress does not activate Nrf2 and does not induce Nrf2 target genes (NQO1, GCLC and HMOX‐1). In cultured vascular smooth muscle cells (VSMCs) derived from young and old M. mulatta , treatment with H 2 O 2 and high glucose significantly increases transcriptional activity of Nrf2 and up‐regulates the expression of Nrf2 target genes in the young but not aged macaques. Taken together, aging is associated with Nrf2 dysfunction in M. mulatta arteries, which likely exacerbates age‐related cellular oxidative stress, promoting NF‐κB activation and vascular inflammation in aging.