Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK
Diabetes. 2013 Jun;62(6):2130-4. doi: 10.2337/db12-1294. Epub 2013 Jan 24.
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.
胰岛素抵抗的特征是内皮细胞产生潜在细胞毒性浓度的活性氧。我们在两种互补的人类胰岛素抵抗体内模型（内皮细胞特异性和全身）中研究了 NADPH 氧化酶 (Nox) ，特别是 Nox2 同工型在超氧生成中的作用。使用三种互补的方法测量超氧，我们证明了胰岛素抵抗的内皮细胞中超氧水平更高，使用 Nox 抑制剂 gp91ds-tat 可以急性和慢性地抑制这种超氧。同样，gp91ds-tat 也可以逆转胰岛素抵抗诱导的内皮介导的血管舒张功能障碍。胰岛素抵抗的内皮细胞中特异性升高的 Nox2 的 siRNA 介导的敲低显著降低了超氧水平。内皮细胞特异性胰岛素抵抗和 Nox2 缺失的双重转基因小鼠显示出减少的超氧生成和改善的血管功能。这项研究确定了 Nox2 作为胰岛素抵抗介导的氧化应激和血管功能障碍的中心分子。它还确立了 Nox2 的药理学抑制作为与胰岛素抵抗相关的血管疾病的新的治疗靶点。
