Pharmacological inhibition of NOX reduces atherosclerotic lesions, vascular ROS and immune-inflammatory responses in diabetic Apoe -/- mice
Pharmacological inhibition of NOX reduces atherosclerotic lesions, vascular ROS and immune-inflammatory responses in diabetic Apoe -/- mice
复制标题
DOI：
10.1007/s00125-013-3118-3
复制
发表时间：
2014-03-01
期刊：
影响因子：
8.2
通讯作者：
Jandeleit-Dahm, K. A.
中科院分区：
文献类型：
--
作者：
Di Marco, E.;Gray, S. P.;Jandeleit-Dahm, K. A.
增强的血管炎症、免疫细胞的渗透和活性氧物种(ROS)的产生增加在糖尿病的促动脉粥样硬化反应中起重要作用。我们评估了NADPH氧化酶(NOX)衍生的ROS在糖尿病加速的动脉粥样硬化中的免疫调节作用。雄性APOE(-/-)小鼠每天服用5剂链脲佐菌素(55 mg kg(-1)day(-1))诱导糖尿病。观察动脉粥样硬化斑块大小、ROS标志物和免疫细胞聚集情况，并对邻近纵隔淋巴结(MeLN)细胞进行流式细胞术分析。用NOX抑制剂GKT137831(每天60 mg/kg；灌胃)给糖尿病和非糖尿病APOE(-/-)小鼠10周，研究了NOX产生的ROS的作用。糖尿病增加了主动脉窦动脉粥样硬化斑块的形成，这与T细胞和CD11c(+)细胞的病变积累增加以及相邻meLN中T细胞的激活改变有关。糖尿病APOE(-/-)小鼠血管ROS产生增加，促炎症标志物单核细胞趋化蛋白1、血管黏附分子1和干扰素-γ表达增加。用GKT137831阻断NOX衍生的ROS可阻止糖尿病引起的动脉粥样硬化斑块面积和相关血管T细胞浸润的增加，并显著减少血管ROS以及炎症和斑块坏死核心区的标志物。糖尿病促进主动脉窦及其相关淋巴组织的促炎免疫反应。这些变化与NOX产生的ROS增加有关。使用NOX抑制剂GKT137831阻断NOX衍生的ROS与减弱免疫反应中的这些变化有关，并减少糖尿病加速的APOE(-/-)小鼠动脉粥样硬化斑块的发展。
Enhanced vascular inflammation, immune cell infiltration and elevated production of reactive oxygen species (ROS) contribute significantly to pro-atherogenic responses in diabetes. We assessed the immunomodulatory role of NADPH oxidase (NOX)-derived ROS in diabetes-accelerated atherosclerosis.Diabetes was induced in male Apoe (-/-) mice with five daily doses of streptozotocin (55 mg kg(-1) day(-1)). Atherosclerotic plaque size, markers of ROS and immune cell accumulation were assessed in addition to flow cytometric analyses of cells isolated from the adjacent mediastinal lymph nodes (meLNs). The role of NOX-derived ROS was investigated using the NOX inhibitor, GKT137831 (60 mg/kg per day; gavage) administered to diabetic and non-diabetic Apoe (-/-) mice for 10 weeks.Diabetes increased atherosclerotic plaque development in the aortic sinus and this correlated with increased lesional accumulation of T cells and CD11c(+) cells and altered T cell activation in the adjacent meLNs. Diabetic Apoe (-/-) mice demonstrated an elevation in vascular ROS production and expression of the proinflammatory markers monocyte chemoattractant protein 1, vascular adhesion molecule 1 and IFN gamma. Blockade of NOX-derived ROS using GKT137831 prevented the diabetes-mediated increase in atherosclerotic plaque area and associated vascular T cell infiltration and also significantly reduced vascular ROS as well as markers of inflammation and plaque necrotic core area.Diabetes promotes pro-inflammatory immune responses in the aortic sinus and its associated lymphoid tissue. These changes are associated with increased ROS production by NOX. Blockade of NOX-derived ROS using the NOX inhibitor GKT137831 is associated with attenuation of these changes in the immune response and reduces the diabetes-accelerated development of atherosclerotic plaques in Apoe (-/-) mice.