Craige Siobhan M, Kant Shashi, Reif Michaella, Chen Kai, Pei Yongmei, Angoff Rebecca, Sugamura Koichi, Fitzgibbons Timothy, Keaney John F
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Free Radic Biol Med. 2015 Dec;89:1-7. doi: 10.1016/j.freeradbiomed.2015.07.004. Epub 2015 Jul 10.
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.
已知血管活性氧（ROS）参与动脉粥样硬化的发生和发展。NADPH氧化酶4（Nox4）是一种组成型活性ROS生成酶，在血管内皮中高度表达。Nox4在生物学特性上具有独特性，并与血管修复有关，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，给Apoe E-/-小鼠+/-内皮Nox4（ApoE-/- + EC Nox4）喂食高胆固醇/高脂肪（西式）饮食24周。与ApoE-/-同窝小鼠相比，在ApoE-/- + EC Nox4小鼠中观察到的动脉粥样硬化病变明显更少，这在主动脉腹部区域最为明显。此外，两组之间T细胞群体的标志物明显不同；与单独的ApoE-/-相比，ApoE-/- + EC Nox4小鼠主动脉中T调节细胞标志物（FoxP3）增加，而T效应细胞标志物（T-bet）减少。我们还观察到，在ApoE-/- + EC Nox4小鼠的血浆和组织中，γ干扰素诱导的单核因子（MIG；CXCL9）减少，MIG是一种已知可募集和激活T细胞的细胞因子。为了进一步研究内皮Nox4与MIG表达之间的联系，我们利用了来自我们的EC Nox4转基因小鼠的培养内皮细胞和过表达Nox4腺病毒的人类细胞。在这些培养细胞中，Nox4的上调减弱了内皮细胞对干扰素-γ的MIG表达。这些数据共同表明，内皮Nox4表达减少MIG产生，并促进有利于修复而非炎症的T细胞分布，从而预防动脉粥样硬化。
