Khambata Rayomand S, Ghosh Suborno M, Rathod Krishnaraj S, Thevathasan Tharssana, Filomena Federica, Xiao Qingzhong, Ahluwalia Amrita
William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
William Harvey Research Institute, Barts & The London Medical School, Queen Mary University of London, London EC1M 6BQ, United Kingdom
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E550-E559. doi: 10.1073/pnas.1613063114. Epub 2017 Jan 5.
Reduced bioavailable nitric oxide (NO) plays a key role in the enhanced leukocyte recruitment reflective of systemic inflammation thought to precede and underlie atherosclerotic plaque formation and instability. Recent evidence demonstrates that inorganic nitrate (NO) through sequential chemical reduction in vivo provides a source of NO that exerts beneficial effects upon the cardiovascular system, including reductions in inflammatory responses. We tested whether the antiinflammatory effects of inorganic nitrate might prove useful in ameliorating atherosclerotic disease in Apolipoprotein (Apo)E knockout (KO) mice. We show that dietary nitrate treatment, although having no effect upon total plaque area, caused a reduction in macrophage accumulation and an elevation in smooth muscle accumulation within atherosclerotic plaques of ApoE KO mice, suggesting plaque stabilization. We also show that in nitrate-fed mice there is reduced systemic leukocyte rolling and adherence, circulating neutrophil numbers, neutrophil CD11b expression, and myeloperoxidase activity compared with wild-type littermates. Moreover, we show in both the ApoE KO mice and using an acute model of inflammation that this effect upon neutrophils results in consequent reductions in inflammatory monocyte expression that is associated with elevations of the antiinflammatory cytokine interleukin (IL)-10. In summary, we demonstrate that inorganic nitrate suppresses acute and chronic inflammation by targeting neutrophil recruitment and that this effect, at least in part, results in consequent reductions in the inflammatory status of atheromatous plaque, and suggest that this effect may have clinical utility in the prophylaxis of inflammatory atherosclerotic disease.
生物可利用的一氧化氮（NO）减少在增强白细胞募集方面起关键作用，而白细胞募集反映了被认为先于动脉粥样硬化斑块形成和不稳定并构成其基础的全身炎症。最近的证据表明，无机硝酸盐（NO）通过体内的顺序化学还原提供了一种NO来源，对心血管系统产生有益影响，包括减少炎症反应。我们测试了无机硝酸盐的抗炎作用是否可能有助于改善载脂蛋白（Apo）E基因敲除（KO）小鼠的动脉粥样硬化疾病。我们发现，饮食硝酸盐处理虽然对总斑块面积没有影响，但可导致ApoE KO小鼠动脉粥样硬化斑块内巨噬细胞积聚减少和平滑肌积聚增加，提示斑块稳定。我们还发现，与野生型同窝小鼠相比，喂食硝酸盐的小鼠全身白细胞滚动和黏附减少、循环中性粒细胞数量减少、中性粒细胞CD11b表达减少以及髓过氧化物酶活性降低。此外，我们在ApoE KO小鼠以及使用急性炎症模型中均发现，对中性粒细胞的这种作用会导致炎症单核细胞表达随之减少，这与抗炎细胞因子白细胞介素（IL）-10升高有关。总之，我们证明无机硝酸盐通过靶向中性粒细胞募集来抑制急性和慢性炎症，并且这种作用至少部分导致动脉粥样硬化斑块炎症状态的随之降低，并表明这种作用可能在预防炎症性动脉粥样硬化疾病方面具有临床应用价值。
