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首页> 外文期刊>Physiological Reports >Heterozygous eNOS deficiency is associated with oxidative stress and endothelial dysfunction in diet‐induced obesity
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Heterozygous eNOS deficiency is associated with oxidative stress and endothelial dysfunction in diet‐induced obesity

机译：饮食引起的肥胖中杂合性eNOS缺乏与氧化应激和内皮功能障碍有关

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AbstractHeterozygous endothelial nitric oxide synthase (eNOS) deficiency is associated with normal endothelium-dependent responses, however, little is known regarding the mechanisms that maintain or impair endothelial function with heterozygous eNOS deficiency. The goals of this study were to (1) determine mechanism(s) which serve to maintain normal endothelial function in the absence of a single eNOS gene; and (2) to determine whether heterozygous eNOS deficiency predisposes blood vessels to endothelial dysfunction in response to a high-fat diet (HFD). Responses of carotid arteries were examined in wild-type (eNOS+/+) and heterozygous eNOS-deficient (eNOS+/−) treated with either vehicle (saline), NG-nitro-L-arginine (L-NNA, 100 μmol/L), an inhibitor of nitric oxide synthase, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 μmol/L), an inhibitor of soluble guanylyl cyclase (sGC), and in eNOS+/+ and eNOS+/− mice fed a control (10%) or a 45% HFD (kcal from fat). Responses to acetylcholine (ACh) were similar in vehicle-treated arteries from eNOS+/+ and eNOS+/− mice, and were equally inhibited by L-NNA and ODQ. Phosphorylation of eNOS Ser1176, a site associated with increased eNOS activity, was significantly greater in eNOS+/− mice most likely as a compensatory response for the loss of a single eNOS gene. In contrast, responses to ACh were markedly impaired in carotid arteries from eNOS+/−, but not eNOS+/+, mice fed a HFD. Vascular superoxide levels as well as plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) were selectively increased in HFD-fed eNOS+/− mice. In reconstitution experiments, IL-6 produced concentration-dependent impairment of endothelial responses as well as greater increases in NADPH-stimulated superoxide levels in arteries from eNOS+/− mice fed a control diet compared to eNOS+/+ mice. Our findings of increased Ser1176-phosphorylation reveal a mechanism by which NOS- and sGC-dependent endothelial function can be maintained with heterozygous eNOS deficiency. In addition, heterozygous eNOS deficiency predisposes blood vessels to developing endothelial dysfunction in response to a HFD. The impairment produced by a HFD in eNOS+/− mice appears to be mediated by IL-6-induced increases in vascular superoxide. These findings serve as an important example of eNOS haploinsufficiency, one that may contribute to the development of carotid artery disease in obese humans.
机译：摘要杂合型内皮一氧化氮合酶（eNOS）缺乏与正常的内皮依赖性反应有关，但是对于杂合型eNOS缺乏维持或损害内皮功能的机制知之甚少。这项研究的目的是（1）确定在没有单个eNOS基因的情况下可维持正常内皮功能的机制; （2）确定杂合性eNOS缺乏是否使血管容易因高脂饮食（HFD）而发生内皮功​​能障碍。用两种媒介物（盐水），N处理的野生型（eNOS + / + ）和杂合的eNOS缺陷型（eNOS +/- ）检查颈动脉的反应。一氧化氮合酶抑制剂或1H- [1,2,4]恶二唑[4,3-a] G -硝基-L-精氨酸（L-NNA，100μmol/ L）喹喔啉-1-酮（ODQ，1μmol/ L），可溶性鸟苷酸环化酶（sGC）抑制剂，在eNOS + / + 和eNOS +/- 小鼠中喂食对照（10％）或45％HFD（脂肪中的大卡）。 eNOS + / + 和eNOS +/- 小鼠经媒介物处理的动脉中对乙酰胆碱（ACh）的反应相似，并且同样受到L-NNA和ODQ的抑制。 eNOS Ser1176（与eNOS活性增加有关的位点）的磷酸化在eNOS +/- 小鼠中明显更高，最有可能是单个eNOS基因丢失的补偿性反应。相比之下，喂食HFD的小鼠的eNOS +/- 而不是eNOS + / + 的颈动脉对ACh的反应明显受损。在喂食HFD的eNOS +/- 小鼠中，血管超氧化物水平和促炎性细胞因子白介素6（IL-6）的血浆水平选择性升高。在重建实验中，与eNOS 喂养对照饮食的小鼠，IL-6产生浓度依赖性的内皮反应损伤，以及NADPH刺激的动脉中超氧化物水平的增加。 > + / + 小鼠。我们发现的增加的Ser1176-磷酸化揭示了一种机制，通过该机制可以维持杂合性eNOS缺乏的NOS和sGC依赖性内皮功能。此外，杂合性eNOS缺乏使血管易于响应HFD而发展为内皮功能障碍。 HFD在eNOS +/- 小鼠中产生的损伤似乎是由IL-6诱导的血管超氧化物增加引起的。这些发现是eNOS单体不足的重要例子，可能导致肥胖的人颈动脉疾病的发展。

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