Vitexin inhibits APEX1 to counteract the flow-induced endothelial inflammation
| Autor: | Yun-Peng Zhang, Yi-Shuan Li, Shu Chien, Run-Ze Tang, Wei Pang, Jing Zhou, Fang-Fang Yang, Juan-Juan Zhu, Dong Wang, Zhi-Tong Jiang, Jia-Nan Zhao, Chuan-Rong Zhao, Yiran Zhou, Xiaohong Wang, Weijuan Yao, Qinghua Cui |
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| Rok vydání: | 2021 |
| Předmět: |
Active Transport
Cell Nucleus Vitexin Inflammation Proinflammatory cytokine Mice chemistry.chemical_compound DNA-(Apurinic or Apyrimidinic Site) Lyase Human Umbilical Vein Endothelial Cells medicine Animals Humans p300-CBP Transcription Factors Apigenin Phosphorylation Multidisciplinary Tumor Necrosis Factor-alpha Chemistry Endothelial Cells Biological Sciences Atherosclerosis Phenotype Cell biology Acetylation Acetyltransferase Tumor necrosis factor alpha medicine.symptom Ligation Protein Binding Signal Transduction |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2115158118 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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