Role of NFκB in age-related vascular endothelial dysfunction in humans

(CVD) are the leading cause of morbidity and mortality in the United States and other industrialized societies. Older age is the major risk factor for development of CVD [1]. Emerging evidence over the past 20 years suggests that the arterial vascular endothelium plays a critical role in the development of CVD, most notably, atherosclerosis. A healthy vascular endothelium is characterized by a tightly regulated balance of pro-and anti-oxidants, vasodilators and vasoconstrictors, and pro-and anti-inflammatory molecules. A diseased or dysfunctional endothelium displays a " pro-atherogenic " phenotype, losing its tightly regulated balance and adopting a pro-oxidant/vasoconstrictor/pro-inflammatory phenotype. A hallmark of arterial endothelial dysfunction is impaired endothelial dependent dilation, which is predictive of future CVD events [1, 2]. Aging leads to impaired endothelial dependent dilation associated elevated oxidative stress and a pro-inflammatory endothelial cell phenotype. Recent studies in humans by our group and by others in rodents suggest a critical role of nuclear factor κB (NFκB) in the pro-inflammatory / pro-oxidant linked suppression of endothelial dependent dilation with advancing aging [3-7]. This perspective will discuss new information concerning the role of increased NFκB signaling in mediating vascular endothelial dysfunction with aging in humans. This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited NFκB is an important transcription factor expressed in all mammalian cell types. It is responsible for regulating gene expression of factors that control cell adhesion, proliferation, inflammation, redox status, and tissue specific enzymes. In arteries, NFκB is thought to promote CVD through its pro-inflammatory, pro-adhesion and pro-oxidant gene transcription. Recent evidence, however, suggests that not all NFκB-mediated gene regulation may be deleterious to the vascular system. For example, acute shear stress evoked increases in endothelial nitric oxide synthase, the enzyme that synthesizes the vascular protective molecule nitric oxide, is NFκB dependent [8]. The complexity in the control of NFκB signaling provides insight into how this transcription factor can have such diversity of regulatory responsibilities. The NFκB activation pathway is triggered by a wide variety of stimuli including inflammatory cytokines, reactive oxygen species, lipids and mechanical forces acting on the vascular endothelial wall leading to stimulation of transmembrane receptors. This triggers intracellular signaling pathways leading to an activation of a kinase (IκK) mediated phosphorylation and degradation of the inhibitor of NFκB (IκB). This results in translocation of …