Salicylate Treatment Improves Age-Associated Vascular Endothelial Dysfunction: Potential Role of Nuclear Factor  B and Forkhead Box O Phosphorylation

Abstract

We hypothesized that I kappa B kinase (IKK)-mediated nuclear factor kappa B and forkhead BoxO3a phosphorylation will be associated with age-related endothelial dysfunction. Endothelium-dependent dilation and aortic protein expression/phosphorylation were determined in young and old male B6D2F1 mice and old mice treated with the IKK inhibitor, salicylate. IKK activation was greater in old mice and was associated with greater nitrotyrosine and cytokines. Endothelium-dependent dilation, nitric oxide (NO), and endothelial NO synthase phosphorylation were lower in old mice. Endothelium-dependent dilation and NO bioavailability were restored by a superoxide dismutase mimetic. Nuclear factor kappa B and forkhead BoxO3a phosphorylation were greater in old and were associated with increased expression/activity of nicotinamide adenine dinucleotide phosphate oxidase and lower manganese superoxide dismutase expression. Salicylate lowered IKK phosphorylation and reversed age-associated changes in nitrotyrosine, endothelium-dependent dilation, NO bioavailability, endothelial NO synthase, nuclear factor kappa B and forkhead BoxO3a phosphorylation, nicotinamide adenine dinucleotide phosphate oxidase, and manganese superoxide dismutase. Increased activation of IKK with advancing age stimulates nuclear factor kappa B and inactivates forkhead BoxO3a. This altered transcription factor activation contributes to a pro-inflammatory/pro-oxidative arterial phenotype that is characterized by increased cytokines and nicotinamide adenine dinucleotide phosphate oxidase and decreased manganese superoxide dismutase leading to oxidative stress-mediated endothelial dysfunction.

You're Only as Old as Your Arteries: Translational Strategies for Preserving Vascular Endothelial Function with Aging

“…In support of these preclinical results, older sedentary men show an endothelial oxidative stress profile featuring increased endothelial cell nitrotyrosine and NADPH oxidase, and reduced circulating endothelium-derived (extracellular) superoxide dismutase activity compared with young controls, whereas older exercising men do not demonstrate these changes (143). Regular aerobic exercise also has potent anti-inflammatory effects on aging arteries (106) and vascular endothelial cells (143), and this may be mediated in part by suppression of NF-B signaling (105,106,143,145,200).…”

“…EDD is impaired in older rodents and humans as a result of reduced NO bioavailability. 105), as inhibition of NFB and/or its downstream mediators, such as tumor necrosis factor-␣ (TNF-␣), reverses age-associated endothelial dysfunction in older rodents and humans (32, 105,129,145). Collectively, these events can be considered adverse vascular aging processes that induce and sustain oxidative stress, inflammation, and endothelial dysfunction (FIGURE 2B).…”

“…generally has not shown efficacy in patients with CVD (52, 95), and their effectiveness for improving age-associated endothelial dysfunction is unclear. On the one hand, acute administration of supra-physiological concentrations of superoxide-scavenging agents (vitamin C, TEMPOL) essentially restores EDD in older humans and mice (56, 105,181), as does single oral ingestion of an antioxidant "cocktail" containing vitamins C and E plus lipoic acid (209). Moreover, short-term (3 wk) oral treatment with TEMPOL, a SOD-mimetic, completely reverses endothelial dysfunction in old mice by restoring NO and mitigating vascular oxidative stress and inflammation (61), and 3 mo of vitamin C supplementation improves endothelial fibrinolytic function in overweight/obese middle-aged men (191).…”

NF-κB — A Key Factor in Atherogenesis and Atheroprogression

“…Multiple upstream pathways might be responsible for activating NF-κB in endothelial cells promoting the development of atherosclerosis. Supporting the critical role of NF-κB in inflammation-dependent endothelial dysfunction is evidence that pharmacological inhibition of NF-κB signaling significantly reduces cytokines and enhances endothelial-dependent dilation in old mice and humans [36][37][38].…”

AMPK activation—protean potential for boosting healthspan

“…This may explain why the diabetic glycemic control achieved with salsalate therapy tends to be less impressive than that seen with metformin or berberine-and much of the glycemic reduction it does achieve may be mediated by downregulation of IkappaB kinase activation (Goldfine et al 2010;Faghihimani et al 2013;Yin et al 1998). Nonetheless, employing salsalate in conjunction with either metformin or berberine may be an attractive option for managing diabetes, vascular disorders, or cancer; (McCarty 2010;Pierce et al 2009;Lesniewski et al 2011;McCarty and Block 2006) these agents may complement each other with respect to AMPK activation, NF-kappaB inhibition, and control of oxidative stress.…”