Endothelial AIP1 Regulates Vascular Remodeling by Suppressing NADPH Oxidase-2.
Endothelial AIP1 Regulates Vascular Remodeling by Suppressing NADPH Oxidase-2.
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内皮 AIP1 通过抑制 NADPH 氧化酶 2 调节血管重塑
DOI：
10.3389/fphys.2018.00396
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发表时间：
2018
影响因子：
4
通讯作者：
Min W
中科院分区：
文献类型：
--
作者：
Zhang J;Chen C;Li L;Zhou HJ;Li F;Zhang H;Yu L;Chen Y;Min W
目的：AIP 1在人动脉粥样硬化斑块中表达下调，小鼠中AIP 1的整体缺失加重了ApoE-KO小鼠模型中的动脉粥样硬化。然而，AIP 1在内皮、血管重塑和相关血管疾病中的直接作用尚未确定。方法和结果：我们使用内皮细胞（EC）特异性AIP 1缺陷（AIP 1-ECKO）小鼠来确定AIP 1在小鼠颈动脉结扎模型中血管重塑和内膜-中膜增厚中的作用，该模型的特征是新生内膜增生和向内血管重塑。与WT同窝小鼠相比，AIP 1-ECKO小鼠在损伤后第2-4周具有2.2倍大的内膜面积和4.4倍厚的内膜，如在具有更多增殖的血管平滑肌细胞（VSMC）的动脉中通过内膜/中膜比率测量的。在血管平滑肌细胞聚集之前，AIP 1-ECKO中内皮细胞中活性氧（ROS）的增加在早期时间点诱导炎症和血管功能障碍。此外，敲低人EC中的AIP 1增强了ROS的产生，这通过共沉默NOX 2而减弱。从机制上讲，AIP 1通过其富含脯氨酸的区域与胞质亚基p47 phox的SH 3结构域结合，以破坏活性NOX 2复合物的形成，从而减弱ROS的产生。结论：我们的研究支持AIP 1通过抑制内皮细胞NOX 2依赖的氧化应激来调节血管重塑和内膜中层增厚。亮点：·在颈动脉结扎模型中，内皮细胞（EC）特异性AIP 1缺陷（AIP 1-ECKO）小鼠的中膜面积更大，血管壁更厚，新生内膜形成增加。在AIP 1-ECKO中，伴随血管功能障碍的早期时间点血管EC中活性氧的产生增加。AIP 1通过其富含脯氨酸的区域与胞质亚基p47 phox的SH 3结构域结合，以破坏活性NOX 2复合物的形成，从而减弱ROS的产生。
Objective: AIP1 expression is downregulated in human atherosclerotic plaques and global deletion of AIP1 in mice exacerbates atherosclerosis in ApoE-KO mouse models. However, the direct role of AIP1 in endothelium, vascular remodeling and associated vascular diseases has not been determined. Approach and Results: We used endothelial cell (EC)-specific AIP1-deficient (AIP1-ECKO) mice to define the role of AIP1 in vascular remodeling and intima-media thickening in a mouse carotid artery ligation model characterized by both neointimal hyperplasia and inward vessel remodeling. Compared to WT littermates, AIP1-ECKO mice had 2.2-fold larger intima area and 4.4-fold thicker intima as measured by intima/media ratio in arteries with more proliferating vascular smooth muscle cells (VSMCs) at week 2–4 post-injury. Increased reactive oxygen species (ROS) in endothelium at early time points induced inflammation and vessel dysfunction in AIP1-ECKO prior to VSMC accumulations. Moreover, knockdown of AIP1 in human EC enhanced ROS generation which was attenuated by co-silencing of NOX2. Mechanistically, AIP1 via its proline-rich region binds to the SH3 domain of cytosolic subunit p47phox to disrupt formation of an active NOX2 complex, attenuating ROS production. Conclusion: Our study supports that AIP1 regulates vascular remodeling with intima-media thickening by suppressing endothelial NOX2-dependent oxidative stress. Highlights: • In a carotid ligation model, endothelial cell (EC)-specific AIP1-deficient (AIP1-ECKO) mice had much larger media area, thicker vessel wall and augmented neointima formation.• Increased production of reactive oxygen species in vascular EC at early time points concomitant with vessel dysfunction in AIP1-ECKO.• AIP1 via its proline-rich region binds to the SH3 domain of cytosolic subunit p47phox to disrupt formation of an active NOX2 complex, attenuating ROS production.
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影响因子：
9.3
作者：
Min W;Pober JS
通讯作者：
Pober JS
影响因子：
2.9
作者：
Nisimoto, Yukio;Jackson, Heather M.;Ogawa, Hisamitsu;Kawahara, Tsukasa;Lambeth, J. David
通讯作者：
Lambeth, J. David
影响因子：
4.3
作者：
Daiber, Andreas
通讯作者：
Daiber, Andreas
DOI：
10.1161/atvbaha.113.301220
发表时间：
2013-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Huang Q;Qin L;Dai S;Zhang H;Pasula S;Zhou H;Chen H;Min W
通讯作者：
Min W
影响因子：
20.1
作者：
Castier, Y;Brandes, RP;Lehoux, S
通讯作者：
Lehoux, S