Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice With Metabolic Disease.
Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice With Metabolic Disease.
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DOI：
10.1161/circresaha.116.309965
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发表时间：
2017-08-18
影响因子：
20.1
通讯作者：
Stepp DW
中科院分区：
文献类型：
--
作者：
Thompson JA;Larion S;Mintz JD;Belin de Chantemèle EJ;Fulton DJ;Stepp DW
代谢性疾病的早期血管变化促使心血管并发症的发展，这主要是由活性氧（ROS）积累驱动的，但过量的ROS在多大程度上来源于特定的Nox亚型仍然不清楚。确定Nox 1在代谢性疾病微血管功能障碍发展中的作用。通过将Nox 1敲除（KO）小鼠与db/db小鼠交配产生四种基因型：瘦型（HdbWnox 1）;瘦型Nox 1 KO（HdbKnox 1）;肥胖型（KdbWnox 1）;肥胖型KK（KdbKnox 1）。通过NMR光谱、葡萄糖耐量试验和血浆分析确定，KW小鼠的肥胖、胰岛素抵抗和血脂异常程度不受Nox 1缺失的影响。KW与HW相比，加压肠系膜动脉中对乙酰胆碱（Ach）的内皮依赖性反应降低（p < 0.01），而KW小鼠中Nox 1的缺失使扩张正常化。抑制一氧化氮（NO）合酶后的血管舒张反应减弱了KK和瘦对照组的Ach反应，但对KW没有影响，将KK恢复的舒张能力归因于NO的正常化。Tempol改善了Ach反应（p < 0.05），组织化学显示KW动物的氧化应激，而Tempol没有影响，并且KK中的ROS染色可以忽略不计。钝的扩张反应，NO供体和肌源性紧张度的损失在KW动物也获救与Nox 1删除。nox 1缺失可降低db/db小鼠的氧化负荷并恢复微血管健康，而不影响代谢功能障碍的程度。因此，靶向抑制Nox 1可能有效预防血管并发症。
Early vascular changes in metabolic disease that precipitate the development of cardiovascular complications are largely driven by reactive oxygen species (ROS) accumulation, yet the extent to which excess ROS derive from specific Nox isoforms remains ill-defined. Identify the role of Nox1 in the development of microvascular dysfunction in metabolic disease. Four genotypes were generated by breeding Nox1 knock-out (KO) mice with db/db mice: lean (HdbWnox1); lean Nox1 KO (HdbKnox1); obese (KdbWnox1); obese KK (KdbKnox1). The degree of adiposity, insulin resistance, and dyslipidemia in KW mice were not influenced by Nox1 deletion as determined by NMR spectroscopy, glucose tolerance tests, and plasma analyses. Endothelium-dependent responses to acetylcholine (Ach) in pressurized mesenteric arteries were reduced in KW vs. HW (p < 0.01), while deletion of Nox1 in KW mice normalized dilation. Vasodilator responses following inhibition of nitric oxide (NO) synthase blunted Ach responses in KK and lean controls, but had no impact in KW, attributing recovered dilatory capacity in KK to normalization of NO. Ach responses were improved (p < 0.05) with Tempol, and histochemistry revealed oxidative stress in KW animals, while Tempol had no impact and ROS staining was negligible in KK. Blunted dilatory responses to a NO donor and loss of myogenic tone in KW animals were also rescued with Nox1 deletion. Nox1 deletion reduces oxidant load and restores microvascular health in db/db mice without influencing the degree of metabolic dysfunction. Therefore, targeted Nox1 inhibition may be effective in the prevention of vascular complications.