Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China.
Proc Natl Acad Sci U S A. 2021 Nov 30;118(48). doi: 10.1073/pnas.2115158118.
Vascular endothelial cells are exposed to shear stresses with disturbed vs. laminar flow patterns, which lead to proinflammatory vs. antiinflammatory phenotypes, respectively. Effective treatment against endothelial inflammation and the consequent atherogenesis requires the identification of new therapeutic molecules and the development of drugs targeting these molecules. Using Connectivity Map, we have identified vitexin, a natural flavonoid, as a compound that evokes the gene-expression changes caused by pulsatile shear, which mimics laminar flow with a clear direction, vs. oscillatory shear (OS), which mimics disturbed flow without a clear direction. Treatment with vitexin suppressed the endothelial inflammation induced by OS or tumor necrosis factor-α. Administration of vitexin to mice subjected to carotid partial ligation blocked the disturbed flow-induced endothelial inflammation and neointimal formation. In hyperlipidemic mice, treatment with vitexin ameliorated atherosclerosis. Using SuperPred, we predicted that apurinic/apyrimidinic endonuclease1 (APEX1) may directly interact with vitexin, and we experimentally verified their physical interactions. OS induced APEX1 nuclear translocation, which was inhibited by vitexin. OS promoted the binding of acetyltransferase p300 to APEX1, leading to its acetylation and nuclear translocation. Functionally, knocking down APEX1 with siRNA reversed the OS-induced proinflammatory phenotype, suggesting that APEX1 promotes inflammation by orchestrating the NF-κB pathway. Animal experiments with the partial ligation model indicated that overexpression of APEX1 negated the action of vitexin against endothelial inflammation, and that endothelial-specific deletion of APEX1 ameliorated atherogenesis. We thus propose targeting APEX1 with vitexin as a potential therapeutic strategy to alleviate atherosclerosis.
血管内皮细胞暴露于切变应力下，切变应力存在紊乱与层流两种流动模式，分别导致促炎与抗炎表型。有效治疗内皮炎症及随之发生的动脉粥样硬化形成，需要鉴定新的治疗分子，并开发针对这些分子的药物。利用 Connectivity Map，我们鉴定出牡荆素（vitexin），一种天然黄酮类化合物，它可引起与搏动切变（pulsatile shear）类似的基因表达变化，搏动切变模仿具有明确方向的层流，而不是模仿无明确方向的振荡切变（oscillatory shear，OS）。牡荆素治疗可抑制 OS 或肿瘤坏死因子-α诱导的内皮炎症。牡荆素给药可阻止颈动脉部分结扎引起的紊乱流诱导的内皮炎症和新生内膜形成。在高脂血症小鼠中，牡荆素治疗可改善动脉粥样硬化。利用 SuperPred，我们预测出核酸内切酶 1（endonuclease 1，APEX1）可能与牡荆素直接相互作用，并通过实验验证了它们的物理相互作用。OS 诱导 APEX1 核转位，而牡荆素可抑制其核转位。OS 促进乙酰转移酶 p300 与 APEX1 结合，导致其乙酰化和核转位。功能上，用 siRNA 敲低 APEX1 可逆转 OS 诱导的促炎表型，表明 APEX1 通过协调 NF-κB 通路促进炎症。部分结扎模型的动物实验表明，APEX1 的过表达否定了牡荆素对内皮炎症的作用，内皮特异性敲除 APEX1 可改善动脉粥样硬化形成。因此，我们提出用牡荆素靶向 APEX1 作为缓解动脉粥样硬化的潜在治疗策略。
