Background: Vascular disease is an important consequence of diabetes and is associated with endothelial dysfunction from hyperglycemia. Other conditions can contribute to endothelial dysfunction and a decrease in NO in endothelial tissue or loss of NO bioavailability. Certain agents and the loss of heat shock proteins which is important for sustained coupled activity contributes to the uncoupling of eNOS and endothelial dysfunction . Uncoupling of eNOS elevates the production of superoxide causing oxidative stress.Both eNOS uncoupling and oxidative stress have been implicated as factors in environmental illness.(Pall)
Heiss recently demonstrated that Nrf2 increases the bioavailability of NO while reducing reactive species and assists in the maintenance of coupling of eNOS. Kim explains that loss of Nrf2 results in increased susceptibility to oxidative and electrophilic stress but also enhances tissue injury because of an impairment in the "adaptive response". Impairments of the Nrf2 system have been associated with a number of diseases such as asthma, atherosclerosis, colitis and COPD. Incidentally, heat shock proteins are included in a class of genes whose expression may be Nrf2-dependant.
Studies have shown that inflammation, endothelial dysfunction, and endothelial damage mediators are upregulated upon exposure to particulate matter (PM) and therefore, environmental pollutants can compromise overall vascular health. Particulate matter is of concern because it is small enough to be carried deep into the lungs where it promotes the production of inflammatory cytokines. In a study published in 2008, TNF and inflammatory cytokines was associated with ultra-fine particulate matter PM2.5 while a 7-day exposure of PM2.5 was negatively associated with the number of white blood cells in exposed children. In addition, these children had increased levels of endothelin-1 and subclinical inflammation. This study suggest that children exposed to PM may be at risk for cardiovascular disease, stroke and other diseases later in life. (Calderón-Garcidueñas) These findings support others that showed higher hospitilizations for children and higher mortality rates in the elderly over 75 years of age exposed to PM2.5. (Jimenez and Linares)
Recent Research:
Title: Activation of Nrf2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease.
According to this author "nrf2 by the dietary activator sulforaphane, limited to concentration ranges found in plasma after consumption of broccoli, increased the expression of protective enzymes under ARE-linked transcriptional control and prevented metabolic dysfunction in endothelial cells induced by hyperglycemia.........decreasing the expression of nrf2 exacerbated ROS production in both normoglycemic and hyperglycemic cultures which provides evidence that ROS generation can be reduced by Nrf2 and that sulforaphane acts through Nrf2 to achieve reductions and prevent endothelial cell damage."
Summary: These findings provide the biochemical basis for the link of a vegetable-rich diet with decreased endothelial dysfunction, including that part of the Mediterranean diet, suggesting that dietary exposure to nrf2 activators derived from cruciferous vegetables may have be involved.
Notes:
- Resveratrol has been demonstrated to improve endothelial function and suppress oxidative stress such as superoxide from NADPH. (Soylemez) In the blog, A Small Book on the Benefits of Resveratrol we explained how other studies have shown some of its activities are regulated through SIRT1 and elevates a number of antioxidants and increases the expression of GCH1 which prevents the elevations in superoxide and (HEIRS Nutrition) alters eNOS expression.
Citation: Xue, M., Qian, Q., Adaikalakoteswari, A., Rabbani, N., Babaei-Jadidi, R., and Thornalley, P. J. (2008). Activation of nf-e2–related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes, 57(10):2809-2817.
http://www.citeulike.org/user/HEIRS/article/3438451
Cheng, J., Ou, J.-S., Singh, H., Falck, J. R., Narsimhaswamy, D., Pritchard, K. A., and Schwartzman, M. L. (2008). 20-hydroxyeicosatetraenoic acid causes endothelial dysfunction via enos uncoupling. Am J Physiol Heart Circ Physiol, 294(2):H1018-1026.
http://www.citeulike.org/user/HEIRS/article/5919352
Kim, J., Cha, Y.-N. N., and Surh, Y.-J. J. (2009). A protective role of nuclear erythroid 2-related factor-2 (nrf2) in inflammatory disorders. Mutation research.
http://www.citeulike.org/user/HEIRS/article/5884341
Pall, Martin. (2007) Explaining "Unexplained Illness". Harrinton Park Press. Pg 34-35.
Kwak, M.-K., Wakabayashi, N., Itoh, K., Motohashi, H., Yamamoto, M., and Kensler, T. W. (2003). Modulation of gene expression by cancer chemopreventive dithiolethiones through the keap1-nrf2 pathway. Journal of Biological Chemistry, 278(10):8135-8145.
http://www.citeulike.org/user/HEIRS/article/883885
Calderón-Garcidueñas, L., Villarreal-Calderon, R., Valencia-Salazar, G., Henríquez-Roldán, C., Gutiérrez-Castrellón, P., Torres-Jardón, R., Osnaya-Brizuela, N., Romero, L., Torres-Jardón, R., Solt, A., and Reed, W. (2008). Systemic inflammation, endothelial dysfunction, and activation in clinically healthy children exposed to air pollutants. Inhalation toxicology, 20(5):499-506.
http://www.citeulike.org/user/HEIRS/article/5919414
Heiss, E. H., Schachner, D., Werner, E. R., and Dirsch, V. M. (2009). Active nf-e2-related factor (nrf2) contributes to keep endothelial no synthase (enos) in the coupled state: the role of reactive oxygen species (ros)-, enos- and heme oxygenase (ho-1) levels. The Journal of biological chemistry.
http://www.citeulike.org/user/HEIRS/article/5886348
Jiménez, E., Linares, C., Rodríguez, L. F., Bleda, M. J., and Díaz, J. (2009). Short-term impact of particulate matter (pm2.5) on daily mortality among the over-75 age group in madrid (spain). The Science of the total environment, 407(21):5486-5492.
http://www.citeulike.org/user/HEIRS/article/5395518
Linares, C. and Díaz, J. (2009). [impact of particulate matter with diameter of less than 2.5 microns [pm2.5] on daily hospital admissions in 0-10-year-olds in madrid. spain [2003-2005]]. Gaceta sanitaria / S.E.S.P.A.S, 23(3):192-197.
http://www.citeulike.org/user/HEIRS/article/5919502
Soylemez, S., Sepici, A., and Akar, F. Resveratrol supplementation gender independently improves endothelial reactivity and suppresses superoxide production in healthy rats. Cardiovascular Drugs and Therapy.
http://www.citeulike.org/user/HEIRS/article/5919555
