Deletion of NoxO1 limits atherosclerosis development in female mice.
Deletion of NoxO1 limits atherosclerosis development in female mice.
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DOI：
10.1016/j.redox.2020.101713
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发表时间：
2020-10
期刊：
影响因子：
11.4
通讯作者：
Brandes RP
中科院分区：
文献类型：
--
作者：
Buchmann GK;Schürmann C;Warwick T;Schulz MH;Spaeth M;Müller OJ;Schröder K;Jo H;Weissmann N;Brandes RP
氧化应激是动脉粥样硬化的一个危险因素。Nox家族的NADPH氧化酶产生ROS，但它们对动脉粥样硬化发展的贡献尚不清楚。Nox2促进动脉粥样硬化，而Nox4限制动脉粥样硬化。虽然Nox1及其细胞质辅助因子主要在上皮细胞中表达，但有人认为Nox1在动脉粥样硬化的发展中起作用。为了进一步确定该同源物的作用，我们借助敲除小鼠确定了其必需的细胞质辅助因子NoxO1在动脉粥样硬化发展中的作用。野生型（WT）和NoxO1敲除小鼠用高脂肪饮食和过表达枯草素/酮素9型（PCSK9）的腺相关病毒（AAV）处理，诱导肝脏低密度脂蛋白（LDL）受体丢失。结果，诱导大量高胆固醇血症，并在3个月内发生自发性动脉粥样硬化。与WT幼崽相比，NoxO1的缺失减少了雌性头臂动脉和主动脉弓的动脉粥样硬化形成，而雄性NoxO1−/−小鼠则没有。这与雌性而非雄性NoxO1−/−小鼠血浆中促炎细胞因子特征的降低有关。血管的MACE-RNAseq没有显示出这一特征，Nox1/NoxO1系统的表达很低甚至无法检测到。支架蛋白NoxO1可能通过减轻全身炎症负担在雌性小鼠动脉粥样硬化发展中起一定作用。活性氧（ROS）被认为促进动脉粥样硬化。NoxO1是激活产生ros的Nox1所需的因子。NoxO1的缺失减轻了雌性小鼠动脉粥样硬化的发展。NoxO1敲除抑制了雌性小鼠血浆中的炎症特征。
Oxidative stress is a risk factor for atherosclerosis. NADPH oxidases of the Nox family produce ROS but their contribution to atherosclerosis development is less clear. Nox2 promotes and Nox4 rather limits atherosclerosis. Although Nox1 with its cytosolic co-factors are largely expressed in epithelial cells, a role for Nox1 for atherosclerosis development was suggested. To further define the role of this homologue, the role of its essential cytosolic cofactor, NoxO1, was determined for atherosclerosis development with the aid of knockout mice. Wildtype (WT) and NoxO1 knockout mice were treated with high fat diet and adeno-associated virus (AAV) overexpressing pro-protein convertase subtilisin/kexin type 9 (PCSK9) to induce hepatic low-density lipoprotein (LDL) receptor loss. As a result, massive hypercholesterolemia was induced and spontaneous atherosclerosis developed within three month. Deletion of NoxO1 reduced atherosclerosis formation in brachiocephalic artery and aortic arch in female but not male NoxO1−/− mice as compared to WT littermates. This was associated with a reduced pro-inflammatory cytokine signature in the plasma of female but not male NoxO1−/− mice. MACE-RNAseq of the vessel did not reveal this signature and the expression of the Nox1/NoxO1 system was low to not detectable. The scaffolding protein NoxO1 plays some role in atherosclerosis development in female mice probably by attenuating the global inflammatory burden. Reactive oxygen species (ROS) are thought to promote atherosclerosis. NoxO1 is a factor required for the activation of the ROS-producing Nox1. Deletion of NoxO1 attenuated atherosclerosis development in female mice. NoxO1 knockout suppressed inflammatory signatures in the female murine plasma.
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影响因子：
1.8
作者：
Hasan-Ali, Hosam;El-Mottaleb, Nashwa A. Abd;Abd-Elsayed, Alaa
通讯作者：
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DOI：
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发表时间：
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Jandeleit-Dahm KAM