Early determinants of H2O2-induced endothelial dysfunction.

Boulden BM, Widder JD, Allen JC, Smith DA, Al-Baldawi RN, Harrison DG, Dikalov SI, Jo H, Dudley SC
Free Radic Biol Med. 2006 41 (5): 810-7

PMID: 16895801 · PMCID: PMC1592456 · DOI:10.1016/j.freeradbiomed.2006.05.030

Reactive oxygen species (ROS) can stimulate nitric oxide (NO(*)) production from the endothelium by transient activation of endothelial nitric oxide synthase (eNOS). With continued or repeated exposure, NO(*) production is reduced, however. We investigated the early determinants of this decrease in NO(*) production. Following an initial H(2)O(2) exposure, endothelial cells responded by increasing NO(*) production measured electrochemically. NO(*) concentrations peaked by 10 min with a slow reduction over 30 min. The decrease in NO(*) at 30 min was associated with a 2.7-fold increase in O(2)(*-) production (p < 0.05) and a 14-fold reduction of the eNOS cofactor, tetrahydrobiopterin (BH(4), p < 0.05). Used as a probe for endothelial dysfunction, the integrated NO(*) production over 30 min upon repeated H(2)O(2) exposure was attenuated by 2.1-fold (p = 0.03). Endothelial dysfunction could be prevented by BH(4) cofactor supplementation, by scavenging O(2)(*-) or peroxynitrite (ONOO(-)), or by inhibiting the NADPH oxidase. Hydroxyl radical (()OH) scavenging did not have an effect. In summary, early H(2)O(2)-induced endothelial dysfunction was associated with a decreased BH(4) level and increased O(2)(*-) production. Dysfunction required O(2)(*-), ONOO(-), or a functional NADPH oxidase. Repeated activation of the NADPH oxidase by ROS may act as a feed forward system to promote endothelial dysfunction.

MeSH Terms (13)

Animals Aorta Biopterin Cattle Endothelium, Vascular Hydrogen Peroxide Hydroxyl Radical Models, Biological Nitric Oxide Oxygen Reactive Oxygen Species Superoxides Time Factors

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