Upregulation of Nox1 in vascular smooth muscle leads to impaired endothelium-dependent relaxation via eNOS uncoupling
Upregulation of Nox1 in vascular smooth muscle leads to impaired endothelium-dependent relaxation via eNOS uncoupling
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DOI：
10.1152/ajpheart.00242.2010
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发表时间：
2010-09-01
影响因子：
4.8
通讯作者：
Griendling, Kathy K.
中科院分区：
文献类型：
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作者：
Dikalova, Anna E.;Gongora, Maria Carolina;Griendling, Kathy K.
Dikalova AE，Gongora MC，Harrison DG，兰贝斯JD，Dikalov S，Griendling KK.血管平滑肌中Nox 1的上调通过eNOS解偶联导致内皮依赖性舒张受损美国生理学杂志心脏循环生理学299：H673-H679，2010年。首次发表于2010年7月16日; doi：10.1152/ajpheart.00242.2010.-最近的研究表明，氧化剂系统相互作用。为了研究血管平滑肌中NADPH氧化酶（Nox）1上调与内皮功能之间的潜在串扰，对在平滑肌细胞中过表达Nox 1的转基因小鼠（Tg（SMCnox 1））进行血管紧张素II（ANG II）诱导的高血压。正如预期的那样，NADPH依赖的超氧化物生成增加Nox 1过表达小鼠的胰腺炎。输注ANG II（0.7 mg.kg（-1）.day（-1））2周，与类似处理的阴性同窝对照相比，可增强NADPH依赖性超氧化物生成和过氧化氢生成。转基因小鼠内皮依赖性舒张功能受损，生物可利用的一氧化氮显著减少。为了检验eNOS解偶联可能导致内皮功能障碍的假设，饮食中补充了四氢生物蝶呤（BH 4）。BH 4降低了主动脉超氧化物的产生，部分恢复了ANG II治疗的Tg（SMCnox 1）小鼠动脉中的生物可利用的一氧化氮，并显着改善了这些小鼠的内皮依赖性舒张。Western印迹分析显示，与野生型小鼠相比，Tg（SMCnox 1）小鼠的eNOS二聚体较少;然而，总eNOS是相等的。与野生型小鼠相比，用eNOS抑制剂N-G-硝基-L-精氨酸甲酯预处理小鼠睾丸可降低Tg（SMCnox 1）小鼠中ANG II诱导的超氧化物产生，表明未偶联的eNOS也是转基因小鼠中超氧化物增加的重要来源。因此，血管平滑肌中Nox 1的过度表达导致响应ANG II的活性氧物质的产生增加，导致eNOS解偶联和一氧化氮生物利用度降低，导致血管舒张受损。
Dikalova AE, Gongora MC, Harrison DG, Lambeth JD, Dikalov S, Griendling KK. Upregulation of Nox1 in vascular smooth muscle leads to impaired endothelium-dependent relaxation via eNOS uncoupling. Am J Physiol Heart Circ Physiol 299: H673-H679, 2010. First published July 16, 2010; doi:10.1152/ajpheart.00242.2010.-Recent work has made it clear that oxidant systems interact. To investigate potential cross talk between NADPH oxidase (Nox) 1 upregulation in vascular smooth muscle and endothelial function, transgenic mice overexpressing Nox1 in smooth muscle cells (Tg(SMCnox1)) were subjected to angiotensin II (ANG II)-induced hypertension. As expected, NADPH-dependent superoxide generation was increased in aortas from Nox1-overexpressing mice. Infusion of ANG II (0.7 mg.kg(-1).day(-1)) for 2 wk potentiated NADPH-dependent superoxide generation and hydrogen peroxide production compared with similarly treated negative littermate controls. Endothelium-dependent relaxation was impaired in transgenic mice, and bioavailable nitric oxide was markedly decreased. To test the hypothesis that eNOS uncoupling might contribute to endothelial dysfunction, the diet was supplemented with tetrahydrobiopterin (BH4). BH4 decreased aortic superoxide production, partially restored bioavailable nitric oxide in aortas of ANG II-treated Tg(SMCnox1) mice, and significantly improved endothelium-dependent relaxation in these mice. Western blot analysis revealed less dimeric eNOS in Tg(SMCnox1) mice compared with the wild-type mice; however, total eNOS was equivalent. Pretreatment of mouse aortas with the eNOS inhibitor N-G-nitro-L-arginine methyl ester decreased ANG II-induced superoxide production in Tg(SMCnox1) mice compared with wild-type mice, indicating that uncoupled eNOS is also a significant source of increased superoxide in transgenic mice. Thus overexpression of Nox1 in vascular smooth muscle leading to enhanced production of reactive oxygen species in response to ANG II causes eNOS uncoupling and a decrease in nitric oxide bioavailability, resulting in impaired vasorelaxation.