Endothelial NADPH oxidase 4 protects ApoE-/- mice from atherosclerotic lesions.
Endothelial NADPH oxidase 4 protects ApoE-/- mice from atherosclerotic lesions.
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DOI：
10.1016/j.freeradbiomed.2015.07.004
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发表时间：
2015-12
影响因子：
7.4
通讯作者：
Keaney JF Jr
中科院分区：
文献类型：
--
作者：
Craige SM;Kant S;Reif M;Chen K;Pei Y;Angoff R;Sugamura K;Fitzgibbons T;Keaney JF Jr
已知血管活性氧（ROS）参与动脉粥样硬化的发生和进展。 NADPH 氧化酶 4 (Nox4) 是一种组成型活性 ROS 产生酶，在血管内皮细胞中高度表达。 Nox4在生物学上是独特的，并且与血管修复有关，然而，Nox4在动脉粥样硬化中的作用尚不清楚。因此，为了确定内皮Nox4对动脉粥样硬化发展的影响，Apoe E−/−小鼠+/-内皮Nox4（ApoE−/−+EC Nox4）被喂食高胆固醇/高脂肪（西方）饮食24周。与 ApoE−/− 同窝小鼠相比，ApoE−/− + EC Nox4 小鼠中观察到的动脉粥样硬化病变明显较少，这在主动脉腹部区域最为明显。此外，各组之间的 T 细胞群标记也存在显着差异。与单独的 ApoE−/− 相比，ApoE−/− + EC Nox4 小鼠的主动脉中 T 调节细胞标记物 (FoxP3) 增加，而 T 效应细胞标记物 (T-bet) 减少。我们还观察到，在 ApoE−/− + EC Nox4 小鼠的血浆和组织中，γ 干扰素 (MIG；CXCL9) 诱导的单核因子减少，γ 干扰素是一种已知可招募和激活 T 细胞的细胞因子。为了进一步研究内皮Nox4和MIG表达之间的联系，我们利用来自EC Nox4转基因小鼠的培养内皮细胞和腺病毒过度表达Nox4的人类细胞。在这些培养的细胞中，Nox4 的上调减弱了内皮细胞响应干扰素-γ 的 MIG 表达。这些数据共同表明，内皮 Nox4 表达减少了 MIG 的产生，并促进 T 细胞分布，有利于修复而不是炎症，从而防止动脉粥样硬化。
Vascular reactive oxygen species (ROS) are known to be involved in atherosclerosis development and progression. NADPH oxidase 4 (Nox4) is a constitutively active ROS-producing enzyme that is highly expressed in the vascular endothelium. Nox4 is unique in its biology and has been implicated in vascular repair, however, the role of Nox4 in atherosclerosis is unknown. Therefore, to determine the effect of endothelial Nox4 on development of atherosclerosis, Apoe E−/− mice +/− endothelial Nox4 (ApoE−/−+EC Nox4) were fed a high cholesterol/high fat (Western) diet for 24 weeks. Significantly fewer atherosclerotic lesions were observed in the ApoE−/− + EC Nox4 mice as compared to the ApoE−/− littermates, which was most striking in the abdominal region of the aorta. In addition, markers of T cell populations were markedly different between the groups; T regulatory cell marker (FoxP3) was increased whereas T effector cell marker (T-bet) was decreased in aorta from ApoE−/− + EC Nox4 mice compared to ApoE−/− alone. We also observed decreased monokine induced by gamma interferon (MIG; CXCL9), a cytokine known to recruit and activate T cells, in plasma and tissue from ApoE−/− + EC Nox4 mice. To further investigate the link between endothelial Nox4 and MIG expression, we utilized cultured endothelial cells from our EC Nox4 transgenic mice and human cells with adenoviral overexpression of Nox4. In these cultured cells, upregulation of Nox4 attenuated endothelial cell MIG expression in response to interferon-gamma. Together these data suggest that endothelial Nox4 expression reduces MIG production and promotes a T cell distribution that favors repair over inflammation, leading to protection from atherosclerosis.