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.
J Gerontol A Biol Sci Med Sci. 2011 Aug;66(8):866-75. doi: 10.1093/gerona/glr092. Epub 2011 May 28.
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.
衰老会促进血管内皮和平滑肌细胞中的氧化应激，从而导致心血管疾病的发生。NF-E2 相关因子 2（Nrf2）是一种转录因子，它在年轻动物的血管中被活性氧激活，导致许多活性氧解毒和抗氧化基因的适应性上调。本研究旨在阐明非人类灵长类动物血管中 Nrf2 驱动的自由基解毒机制的稳态作用与年龄相关的变化。我们发现，与年轻猕猴（年龄：~10 岁）的血管相比，老年猕猴（年龄：≥20 岁）的颈动脉表现出明显的氧化应激（表现为 8-异前列腺素 F2α 和 4-HNE 含量增加，谷胱甘肽和抗坏血酸水平降低），这与氧化还原敏感的促炎转录因子核因子-κB 的激活有关。然而，与年龄相关的氧化应激不会激活 Nrf2，也不会诱导 Nrf2 靶基因（NQO1、GCLC 和 HMOX1）。在源自年轻 M mulatta 的培养血管平滑肌细胞（VSMCs）中，H2O2 和高葡萄糖处理显著增加了 Nrf2 的转录活性，并上调了 Nrf2 靶基因的表达。相比之下，在源自老年猕猴的培养血管平滑肌细胞中，H2O2 和高葡萄糖诱导的 Nrf2 活性和 Nrf2 驱动的基因表达减弱。与源自年轻 M mulatta 的血管平滑肌细胞相比，高葡萄糖诱导的 H2O2 产生在老年血管平滑肌细胞中显著增加。综上所述，衰老与 M mulatta 动脉中的 Nrf2 功能障碍有关，这可能会加剧与年龄相关的细胞氧化应激，促进核因子-κB 的激活和衰老中的血管炎症。
