MD2 Blockage Protects Obesity-Induced Vascular Remodeling via Activating AMPK/Nrf2
MD2 Blockage Protects Obesity-Induced Vascular Remodeling via Activating AMPK/Nrf2
复制标题
MD2 阻断通过激活 AMPK/Nrf2 保护肥胖引起的血管重塑
DOI：
10.1002/oby.21916
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发表时间：
2017-09-01
期刊：
影响因子：
6.9
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Wang, Lintao;Han, Jibo;Liang, Guang
肥胖和游离脂肪酸（FFA）水平升高与血管氧化应激和重构密切相关。髓样分化2 （Myeloid differentiation 2, MD2）是先天免疫中的一种重要蛋白，是内毒素脂多糖反应所必需的。这项研究表明棕榈酸（PA）也与MD2结合，引发心脏炎症损伤。然而，目前尚不清楚MD2是否在非炎症系统中发挥作用，如肥胖和ffa相关的氧化应激参与血管重塑和损伤。本研究的目的是研究MD2是否参与活性氧的增加和血管重塑。方法采用C57BL/6基因背景的MD2（-/-）小鼠和野生型仔鼠分别饲喂高脂饲料（HFD），建立肥胖诱导的血管重构。采用PA诱导大鼠主动脉内皮细胞（RAECs）和血管平滑肌细胞（VSMCs）氧化应激损伤。结果在体内，MD2缺乏显著降低hfd诱导的血管氧化应激、纤维化和重塑，并伴有amp活化激酶（AMPK）激活和核因子红细胞（Nrf2）上调。在VSMCs和raec中，通过中和MD2单克隆抗体或小干扰RNA敲低抑制MD2可显著激活AMPK/ nrf2信号通路，减轻pa诱导的氧化应激和细胞损伤。结论MD2的缺失或抑制通过激活AMPK/ nrf2信号通路，对HFD/ ffa诱导的血管氧化应激和重构具有保护作用。
ObjectiveObesity and increased free fatty acid (FFA) levels are tightly linked with vascular oxidative stress and remodeling. Myeloid differentiation 2 (MD2), an important protein in innate immunity, is requisite for endotoxin lipopolysaccharide responsiveness. This study shows that palmitic acid (PA) also bonds to MD2, initiating cardiac inflammatory injury. However, it is not clear whether MD2 plays a role in noninflammatory systems such as obesity- and FFA-related oxidative stress involved in vascular remodeling and injury. The aim of this study is to examine whether MD2 participates in reactive oxygen species increase and vascular remodeling.MethodsMale MD2(-/-) mice and wild-type littermates with a C57BL/6 background were fed a high-fat diet (HFD) to establish obesity-induced vascular remodeling. Rat aortic endothelial cells (RAECs) and vascular smooth muscle cells (VSMCs) were treated with PA to induce oxidative stress and injury.ResultsIn vivo, MD2 deficiency significantly reduced HFD-induced vascular oxidative stress, fibrosis, and remodeling, accompanied with AMP-activated kinase (AMPK) activation and nuclear factor erythroid (Nrf2) upregulation. In VSMCs and RAECs, inhibition of MD2 by neutralizing monoclonal antibody to MD2 or small interfering RNA knockdown significantly activated the AMPK/Nrf2-signaling pathway and reduced PA-induced oxidative stress and cell injury.ConclusionsIt was demonstrated that the deletion or inhibition of MD2 protects against HFD/FFA-induced vascular oxidative stress and remodeling by activating the AMPK/Nrf2-signaling pathway.