Nox4 Is a Protective Reactive Oxygen Species Generating Vascular NADPH Oxidase
Nox4 Is a Protective Reactive Oxygen Species Generating Vascular NADPH Oxidase
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DOI：
10.1161/circresaha.112.267054
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发表时间：
2012-04-27
影响因子：
20.1
通讯作者：
Brandes, Ralf P.
中科院分区：
文献类型：
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作者：
Schroeder, Katrin;Zhang, Min;Brandes, Ralf P.
理由：Nox4是血管中H2O2的来源，其功能尚不清楚。其他Nox蛋白被确定为内皮功能障碍的介质。目的：用全局和他莫昔芬诱导的Nox4（-/-）小鼠，研究Nox4在缺血或血管紧张素II引起的应激增加情况下的功能。方法与结果：Nox4在内皮细胞中高表达，参与H2O2的形成。Nox4（-/-）小鼠表现出血管生成减弱（股动脉结扎），而对照组小鼠的peg -过氧化氢酶处理也有类似的效果。低浓度H2O2能减弱和恢复培养的Nox4（-/-）肺内皮细胞（LECs）的管状形成，而peg -过氧化氢酶则能减弱对照组LECs的管状形成。血管紧张素II输注作为氧化应激模型。与野生型相比，诱导型nox4缺失动物的主动脉出现炎症增加、中度肥大和内皮功能障碍。在机制上，Nox4的缺失导致内皮细胞一氧化氮合酶表达、一氧化氮生成和血红素加氧酶-1 （HO-1）表达的降低，这与细胞凋亡和炎症激活有关。HO-1的表达受Nrf-2控制。因此，Nox4缺陷的LECs表现出Nrf-2蛋白水平降低，Nox4的缺失降低了Nrf-2报告基因的活性。在血管紧张素II输注模型中，HO-1诱导剂hemin可阻断Nox4缺失诱导的血管肥大，HO-1产物一氧化碳可阻断Nox4缺失诱导的LECs细胞凋亡。结论：内源性Nox4在缺血或炎症应激时具有保护血管的作用。与Nox1和Nox2不同，这种特殊的NADPH氧化酶因此可能具有保护血管的功能。（Circ Res. 2012;110:1217-1225.）
Rationale: The function of Nox4, a source of vascular H2O2, is unknown. Other Nox proteins were identified as mediators of endothelial dysfunction.Objective: We determined the function of Nox4 in situations of increased stress induced by ischemia or angiotensin II with global and tamoxifen-inducible Nox4(-/-) mice.Methods and Results: Nox4 was highly expressed in the endothelium and contributed to H2O2 formation. Nox4(-/-) mice exhibited attenuated angiogenesis (femoral artery ligation) and PEG-catalase treatment in control mice had a similar effect. Tube formation in cultured Nox4(-/-) lung endothelial cells (LECs) was attenuated and restored by low concentrations of H2O2, whereas PEG-catalase attenuated tube formation in control LECs. Angiotensin II infusion was used as a model of oxidative stress. Compared to wild-type, aortas from inducible Nox4-deficient animals had development of increased inflammation, media hypertrophy, and endothelial dysfunction. Mechanistically, loss of Nox4 resulted in reduction of endothelial nitric oxide synthase expression, nitric oxide production, and heme oxygenase-1 (HO-1) expression, which was associated with apoptosis and inflammatory activation. HO-1 expression is controlled by Nrf-2. Accordingly, Nox4-deficient LECs exhibited reduced Nrf-2 protein level and deletion of Nox4 reduced Nrf-2 reporter gene activity. In vivo treatment with hemin, an inducer of HO-1, blocked the vascular hypertrophy induced by Nox4 deletion in the angiotensin II infusion model and carbon monoxide, the product of HO-1, blocked the Nox4-deletion-induced apoptosis in LECs.Conclusion: Endogenous Nox4 protects the vasculature during ischemic or inflammatory stress. Different from Nox1 and Nox2, this particular NADPH oxidase therefore may have a protective vascular function. (Circ Res. 2012;110:1217-1225.)