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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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We found that endothelial dependent dilation was impaired in older adults and was associated with increased nuclear translocation of NFκB in their vascular endothelial cells... We also demonstrated that this increased nuclear localization was associated with a decrease in expression of IκBα... This overall activation of NFκB was associated with an increase in endothelial cell expression of the pro-inflammatory NFκB transcripts TNF-α, IL-6 and MCP-1, but not RAGE or cyclooxygenase... These results were the first to demonstrate that healthy human aging is associated with NFκB activation and selective upregulation of inflammatory proteins in the vascular endothelium... One possibility was that NFκB activation increased oxidative stress, which, in turn, caused vascular endothelial dysfunction with aging... Initial evidence for a role of NFκB signaling in age-associated vascular oxidative stress was provided by Donato et al.... In that study, we found that total NFκB expression was positively related to nitrotyrosine, a marker of cellular oxidative stress, in vascular endothelial cells obtained from groups of young and older healthy adults... Taken together, these findings provide experimental support for the idea that NFκB-dependent vascular inflammation tonically impairs vascular endothelial function with aging in humans by stimulating oxidative stress... 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)... 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... 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.

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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.

We found that endothelial dependent dilation was impaired in older adults and was associated with increased nuclear translocation of NFκB in their vascular endothelial cells... We also demonstrated that this increased nuclear localization was associated with a decrease in expression of IκBα... This overall activation of NFκB was associated with an increase in endothelial cell expression of the pro-inflammatory NFκB transcripts TNF-α, IL-6 and MCP-1, but not RAGE or cyclooxygenase... These results were the first to demonstrate that healthy human aging is associated with NFκB activation and selective upregulation of inflammatory proteins in the vascular endothelium... One possibility was that NFκB activation increased oxidative stress, which, in turn, caused vascular endothelial dysfunction with aging... Initial evidence for a role of NFκB signaling in age-associated vascular oxidative stress was provided by Donato et al.... In that study, we found that total NFκB expression was positively related to nitrotyrosine, a marker of cellular oxidative stress, in vascular endothelial cells obtained from groups of young and older healthy adults... Taken together, these findings provide experimental support for the idea that NFκB-dependent vascular inflammation tonically impairs vascular endothelial function with aging in humans by stimulating oxidative stress... 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)... 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... 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.

Show MeSH
Related in: MedlinePlus