Modeling of biopterin-dependent pathways of eNOS for nitric oxide and superoxide production.
Modeling of biopterin-dependent pathways of eNOS for nitric oxide and superoxide production.
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DOI：
10.1016/j.freeradbiomed.2011.06.009
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发表时间：
2011-10-01
影响因子：
7.4
通讯作者：
Kavdia M
中科院分区：
文献类型：
--
作者：
Kar S;Kavdia M
内皮功能障碍与氧化应激增加和低NO生物利用度有关。eNOS解偶联被认为是内皮细胞氧化应激的重要因素。在增加的氧化应激下，eNOS辅因子BH 4被氧化为二氢生物蝶呤（BH 2），其与BH 4竞争结合eNOS，导致eNOS解偶联和NO产生减少。在确定eNOS解偶联程度中，BH 4与氧化生物蝶呤的比率与总生物蝶呤的绝对水平的重要性仍有待确定。我们开发了一个计算模型来模拟eNOS的NO和O2·−产生的生化途径的动力学，以了解BH 4可用性和总生物蝶呤（TBP）浓度对eNOS解偶联的作用。NO、O2·−、ONOO−、O2、CO2和BH 4的下游反应也被模拟。该模型预测，较低的[BH 4]/[TBP]比率会降低NO的产生，但会增加eNOS的O2·−产生。NO和O2·−的产生速率在1.5 µM以上是独立的[TBP]。结果表明，eNOS解偶联是BH 4/TBP比值降低的结果，并且只有当BH 4/TBP比值增加时，补充BH 4才可能有效。本研究的结果将有助于了解内皮功能障碍的机制。
Endothelial dysfunction is associated with increase in oxidative stress and low NO bioavailability. The eNOS uncoupling is considered an important factor in endothelial cell oxidative stress. Under increased oxidative stress, the eNOS cofactor BH4 is oxidized to dihydrobiopterin (BH2), which competes with BH4 for binding to eNOS, resulting in eNOS uncoupling and reduction in NO production. The importance of the ratio of BH4 to oxidized biopterins versus absolute levels of total biopterin in determining extent of eNOS uncoupling remains to be determined. We have developed a computational model to simulate the kinetics of the biochemical pathways of eNOS for both NO and O2•− production to understand the role of BH4 availability and total biopterin (TBP) concentration on eNOS uncoupling. The downstream reactions of NO, O2•−, ONOO−, O2, CO2 and BH4 were also modeled. The model predicted that a lower [BH4]/[TBP] ratio decreased NO production but increased O2•− production from eNOS. The NO and O2•− production rates were independent above 1.5 µM [TBP]. The results indicate that eNOS uncoupling is a result of a decrease in BH4/TBP ratio and a supplementation of BH4 might be effective only when the BH4/TBP ratio increases. The results from the current study will help understand the mechanism of endothelial dysfunction.