Nox2 NADPH oxidase has a critical role in insulin resistance-related endothelial cell dysfunction.
Nox2 NADPH oxidase has a critical role in insulin resistance-related endothelial cell dysfunction.
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DOI：
10.2337/db12-1294
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发表时间：
2013-06
期刊：
影响因子：
7.7
通讯作者：
Kearney MT
中科院分区：
文献类型：
--
作者：
Sukumar P;Viswambharan H;Imrie H;Cubbon RM;Yuldasheva N;Gage M;Galloway S;Skromna A;Kandavelu P;Santos CX;Gatenby VK;Smith J;Beech DJ;Wheatcroft SB;Channon KM;Shah AM;Kearney MT
胰岛素抵抗的特征是内皮细胞产生过多的潜在细胞毒性浓度的活性氧。我们在两个互补的人胰岛素抵抗体内模型（内皮特异性模型和全身模型）中研究了 NADPH 氧化酶 (Nox) 特别是 Nox2 同工型在超氧化物生成中的作用。使用三种互补方法测量超氧化物，我们证明胰岛素抵抗内皮细胞中的超氧化物水平较高，使用 Nox 抑制剂 gp91ds-tat 可以对超氧化物进行急性和慢性药理学抑制。同样，胰岛素抵抗引起的内皮介导的血管舒张功能受损也可以使用 gp91ds-tat 来逆转。 siRNA 介导的 Nox2 敲低（在胰岛素抵抗内皮细胞中特异性升高）显着降低了超氧化物水平。具有内皮特异性胰岛素抵抗和 Nox2 缺失的双转基因小鼠表现出超氧化物产生减少和血管功能改善。这项研究确定 Nox2 是胰岛素抵抗介导的氧化应激和血管功能障碍的中心分子。它还将 Nox2 的药理学抑制确立为胰岛素抵抗相关血管疾病的新治疗靶点。
Insulin resistance is characterized by excessive endothelial cell generation of potentially cytotoxic concentrations of reactive oxygen species. We examined the role of NADPH oxidase (Nox) and specifically Nox2 isoform in superoxide generation in two complementary in vivo models of human insulin resistance (endothelial specific and whole body). Using three complementary methods to measure superoxide, we demonstrated higher levels of superoxide in insulin-resistant endothelial cells, which could be pharmacologically inhibited both acutely and chronically, using the Nox inhibitor gp91ds-tat. Similarly, insulin resistance–induced impairment of endothelial-mediated vasorelaxation could also be reversed using gp91ds-tat. siRNA-mediated knockdown of Nox2, which was specifically elevated in insulin-resistant endothelial cells, significantly reduced superoxide levels. Double transgenic mice with endothelial-specific insulin resistance and deletion of Nox2 showed reduced superoxide production and improved vascular function. This study identifies Nox2 as the central molecule in insulin resistance–mediated oxidative stress and vascular dysfunction. It also establishes pharmacological inhibition of Nox2 as a novel therapeutic target in insulin resistance–related vascular disease.
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影响因子：
7.7
作者：
Imrie H;Viswambharan H;Sukumar P;Abbas A;Cubbon RM;Yuldasheva N;Gage M;Smith J;Galloway S;Skromna A;Rashid ST;Futers TS;Xuan S;Gatenby VK;Grant PJ;Channon KM;Beech DJ;Wheatcroft SB;Kearney MT
通讯作者：
Kearney MT
影响因子：
37.8
作者：
Silver, Annemarie E.;Beske, Stacy D.;Seals, Douglas R.
通讯作者：
Seals, Douglas R.
影响因子：
64.8
作者：
Kahn, Steven E.;Hull, Rebecca L.;Utzschneider, Kristina M.
通讯作者：
Utzschneider, Kristina M.
影响因子：
120.1
作者：
Drummond, Grant R.;Selemidis, Stavros;Griendling, Kathy K.;Sobey, Christopher G.
通讯作者：
Sobey, Christopher G.
影响因子：
168.9
作者：
Booth, Gillian L.;Kapral, Moira K.;Tu, Jack V.
通讯作者：
Tu, Jack V.