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Role of NFkappaB in age-related vascular endothelial dysfunction in humans.

Donato AJ, Pierce GL, Lesniewski LA, Seals DR - Aging (Albany NY) (2009)

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Physiology, University of Colorado, Boulder, CO 80309, USA. tony.donato@colorado.edu

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Recently, we demonstrated that total NFκB protein was elevated in vascular endothelial cells collected in obese pro-inflammatory gene expression... We found that endothelial dependent translocation of NFκB in their vascular endothelial cells... expression of the pro-inflammatory NFκB transcripts TNF-α, IL-6 and MCP-1, but not RAGE or cyclooxygenase... These results were cellular oxidative stress, in vascular endothelial cells obtained from groups Interestingly, acute intravenous infusion of the potent antioxidant, vitamin C, improved endothelial dependent dilation during placebo but did not augment dilation further it during the Salsalate condition... Salsalate also reduced important role in NFκB in mediating vascular endothelial dysfunction in humans by stimulating inflammation and oxidative stress (Figure 1)... Our results this area are the mechanisms by which increases in NFκB nuclear translocation in vascular endothelial cells of older adults

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Depicts the working hypothesis of how vascular aging induces feed forward                                            NFκB signaling that                                            is pro-oxidant and pro-inflammatory leading to endothelial dysfunction and                                            atherosclerosis susceptibility. IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; NFκB, nuclear factor κB; ROS, reactive oxygen species; CVD, cardiovascular disease.
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Figure 1: Depicts the working hypothesis of how vascular aging induces feed forward NFκB signaling that is pro-oxidant and pro-inflammatory leading to endothelial dysfunction and atherosclerosis susceptibility. IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; NFκB, nuclear factor κB; ROS, reactive oxygen species; CVD, cardiovascular disease.

Mentions: In summary, NFκB is a key regulator of inflammation and oxidative stress. As a result of its unique ability to respond to both redox and inflammatory signaling in a cell, NFκB provides an effective "transducer" for feed forward activation of these processes. Recent findings from our laboratory provide evidence for an important role in NFκB in mediating vascular endothelial dysfunction in humans by stimulating inflammation and oxidative stress (Figure 1). Our results provide an experimental basis for future basic and clinical research studies focusing on the contribution of NFκB signaling to vascular aging. Basic research questions include the need for a greater understanding of the nuclear regulation of NFκB promoter binding and gene transcription in aging arteries. Among the key questions in this area are the mechanisms by which increases in NFκB nuclear translocation in vascular endothelial cells of older adults could lead to selective activation of genes involved in inflammation and oxidative stress. The roles of histone modification, DNA methylation, and transcription factor acetylation in such specific regulation of gene expression are worthy of attention. In cell culture, these processes modify NFκB promoter binding, but it is unknown how these mechanisms affect the vascular endothelium with aging. Clinical research directions could include determining if IκK inhibitors, such as salsalate, are viable as long term interventions to reduce tissue specific oxidative stress and inflammation with aging and other age-related disease states. Inhibiting NFκB signaling might limit the vicious cycles of inflammation and oxidative stress, in part by interrupting synergistic crosstalk between these two processes. Thus, modulation of NFκB may be viewed as a potential therapeutic target in the prevention of arterial aging.


Role of NFkappaB in age-related vascular endothelial dysfunction in humans.

Donato AJ, Pierce GL, Lesniewski LA, Seals DR - Aging (Albany NY) (2009)

Depicts the working hypothesis of how vascular aging induces feed forward                                            NFκB signaling that                                            is pro-oxidant and pro-inflammatory leading to endothelial dysfunction and                                            atherosclerosis susceptibility. IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; NFκB, nuclear factor κB; ROS, reactive oxygen species; CVD, cardiovascular disease.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806047&req=5

Figure 1: Depicts the working hypothesis of how vascular aging induces feed forward NFκB signaling that is pro-oxidant and pro-inflammatory leading to endothelial dysfunction and atherosclerosis susceptibility. IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; NFκB, nuclear factor κB; ROS, reactive oxygen species; CVD, cardiovascular disease.
Mentions: In summary, NFκB is a key regulator of inflammation and oxidative stress. As a result of its unique ability to respond to both redox and inflammatory signaling in a cell, NFκB provides an effective "transducer" for feed forward activation of these processes. Recent findings from our laboratory provide evidence for an important role in NFκB in mediating vascular endothelial dysfunction in humans by stimulating inflammation and oxidative stress (Figure 1). Our results provide an experimental basis for future basic and clinical research studies focusing on the contribution of NFκB signaling to vascular aging. Basic research questions include the need for a greater understanding of the nuclear regulation of NFκB promoter binding and gene transcription in aging arteries. Among the key questions in this area are the mechanisms by which increases in NFκB nuclear translocation in vascular endothelial cells of older adults could lead to selective activation of genes involved in inflammation and oxidative stress. The roles of histone modification, DNA methylation, and transcription factor acetylation in such specific regulation of gene expression are worthy of attention. In cell culture, these processes modify NFκB promoter binding, but it is unknown how these mechanisms affect the vascular endothelium with aging. Clinical research directions could include determining if IκK inhibitors, such as salsalate, are viable as long term interventions to reduce tissue specific oxidative stress and inflammation with aging and other age-related disease states. Inhibiting NFκB signaling might limit the vicious cycles of inflammation and oxidative stress, in part by interrupting synergistic crosstalk between these two processes. Thus, modulation of NFκB may be viewed as a potential therapeutic target in the prevention of arterial aging.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Physiology, University of Colorado, Boulder, CO 80309, USA. tony.donato@colorado.edu

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Recently, we demonstrated that total NFκB protein was elevated in vascular endothelial cells collected in obese pro-inflammatory gene expression... We found that endothelial dependent translocation of NFκB in their vascular endothelial cells... expression of the pro-inflammatory NFκB transcripts TNF-α, IL-6 and MCP-1, but not RAGE or cyclooxygenase... These results were cellular oxidative stress, in vascular endothelial cells obtained from groups Interestingly, acute intravenous infusion of the potent antioxidant, vitamin C, improved endothelial dependent dilation during placebo but did not augment dilation further it during the Salsalate condition... Salsalate also reduced important role in NFκB in mediating vascular endothelial dysfunction in humans by stimulating inflammation and oxidative stress (Figure 1)... Our results this area are the mechanisms by which increases in NFκB nuclear translocation in vascular endothelial cells of older adults

Show MeSH
Related in: MedlinePlus