Abstract：
BACKGROUND: Pentamethylquercetin (PMQ) is a natural polymethyl flavonoid that possesses anti-apoptotic and other biological properties. Abdominal aortic aneurysm (AAA), a fatal vascular disease with a high risk of rupture, is associated with phenotypic switching and apoptosis of medial vascular smooth muscle cells (VSMCs). This study aimed to investigate the protective effects of PMQ on the development of AAA and the underlying mechanism.
METHODS: ApoE-/- mice were continuously infused with angiotensin II (Ang II) for 4 weeks to develop the AAA model. Intragastric administration of PMQ was initiated 5 days before Ang II infusion and continued for 4 weeks. In vitro, VSMCs were cultured and pretreated with PMQ, stimulated with Ang II. Real-time PCR, western blotting, and immunofluorescence staining were used to examine the roles and mechanisms of PMQ on the phenotypic switching and apoptosis of VSMCs.
RESULTS: PMQ dose-dependently reduced the incidence of Ang II-induced AAA, aneurysm diameter enlargement, elastin degradation, VSMCs phenotypic switching and apoptosis. Furthermore, PMQ also inhibited phenotypic switching and apoptosis in Ang II-stimulated VSMCs. PMQ exerted protective effects by regulating the C/EBPβ/PTEN/AKT/GSK-3β axis. AAV-mediated overexpression of PTEN reduced the therapeutic effects of PMQ in the AAA model mice, suggesting that the effects of PMQ on Ang II-mediated AAA formation were related to the PTEN/AKT/GSK-3β axis. PMQ inhibited VSMCs phenotypic switching and apoptosis by bounding to C/EBPβ at Lys253 with hydrogen bond to regulate C/EBPβ nuclear translocation and PTEN/AKT/GSK-3β axis, thereby inhibiting Ang II-induced AAA formation.
CONCLUSIONS: Pentamethylquercetin inhibits angiotensin II-induced abdominal aortic aneurysm formation by bounding to C/EBPβ at Lys253. Therefore, PMQ prevents the formation of AAA and reduces the incidence of AAA.
METHODS: ApoE-/- mice were continuously infused with angiotensin II (Ang II) for 4 weeks to develop the AAA model. Intragastric administration of PMQ was initiated 5 days before Ang II infusion and continued for 4 weeks. In vitro, VSMCs were cultured and pretreated with PMQ, stimulated with Ang II. Real-time PCR, western blotting, and immunofluorescence staining were used to examine the roles and mechanisms of PMQ on the phenotypic switching and apoptosis of VSMCs.
RESULTS: PMQ dose-dependently reduced the incidence of Ang II-induced AAA, aneurysm diameter enlargement, elastin degradation, VSMCs phenotypic switching and apoptosis. Furthermore, PMQ also inhibited phenotypic switching and apoptosis in Ang II-stimulated VSMCs. PMQ exerted protective effects by regulating the C/EBPβ/PTEN/AKT/GSK-3β axis. AAV-mediated overexpression of PTEN reduced the therapeutic effects of PMQ in the AAA model mice, suggesting that the effects of PMQ on Ang II-mediated AAA formation were related to the PTEN/AKT/GSK-3β axis. PMQ inhibited VSMCs phenotypic switching and apoptosis by bounding to C/EBPβ at Lys253 with hydrogen bond to regulate C/EBPβ nuclear translocation and PTEN/AKT/GSK-3β axis, thereby inhibiting Ang II-induced AAA formation.
CONCLUSIONS: Pentamethylquercetin inhibits angiotensin II-induced abdominal aortic aneurysm formation by bounding to C/EBPβ at Lys253. Therefore, PMQ prevents the formation of AAA and reduces the incidence of AAA.
摘要：
背景：五甲基槲皮素（PMQ）是一种具有抗凋亡和其他生物学特性的天然多甲基类黄酮。腹主动脉瘤(AAA),一种具有高破裂风险的致命血管疾病，与内侧血管平滑肌细胞（VSMC）的表型转换和凋亡有关。本研究旨在探讨PMQ对AAA发生发展的保护作用及其机制。
方法：ApoE-/-小鼠连续输注血管紧张素II（AngII）4周以建立AAA模型。在AngII输注前5天开始胃内给药PMQ，并持续4周。体外，培养VSMC并用PMQ预处理，用AngII刺激。实时PCR,西方印迹,免疫荧光染色检测PMQ在VSMCs表型转换和凋亡中的作用及机制。
结果：PMQ剂量依赖性地降低了AngII诱导的AAA的发生率，动脉瘤直径扩大，弹性蛋白降解，VSMCs表型转换和凋亡。此外，PMQ还抑制AngII刺激的VSMC中的表型转换和凋亡。PMQ通过调节C/EBPβ/PTEN/AKT/GSK-3β轴发挥保护作用。AAV介导的PTEN过表达降低了PMQ在AAA模型小鼠中的治疗作用,提示PMQ对AngII介导的AAA形成的影响与PTEN/AKT/GSK-3β轴有关。PMQ通过在Lys253处以氢键结合C/EBPβ来调节C/EBPβ核易位和PTEN/AKT/GSK-3β轴，从而抑制VSMCs表型转换和凋亡，从而抑制AngII诱导的AAA形成。
结论：五甲基槲皮素通过在Lys253处与C/EBPβ结合而抑制血管紧张素II诱导的腹主动脉瘤形成。因此,PMQ防止AAA的形成并降低AAA的发生率。
方法：ApoE-/-小鼠连续输注血管紧张素II（AngII）4周以建立AAA模型。在AngII输注前5天开始胃内给药PMQ，并持续4周。体外，培养VSMC并用PMQ预处理，用AngII刺激。实时PCR,西方印迹,免疫荧光染色检测PMQ在VSMCs表型转换和凋亡中的作用及机制。
结果：PMQ剂量依赖性地降低了AngII诱导的AAA的发生率，动脉瘤直径扩大，弹性蛋白降解，VSMCs表型转换和凋亡。此外，PMQ还抑制AngII刺激的VSMC中的表型转换和凋亡。PMQ通过调节C/EBPβ/PTEN/AKT/GSK-3β轴发挥保护作用。AAV介导的PTEN过表达降低了PMQ在AAA模型小鼠中的治疗作用,提示PMQ对AngII介导的AAA形成的影响与PTEN/AKT/GSK-3β轴有关。PMQ通过在Lys253处以氢键结合C/EBPβ来调节C/EBPβ核易位和PTEN/AKT/GSK-3β轴，从而抑制VSMCs表型转换和凋亡，从而抑制AngII诱导的AAA形成。
结论：五甲基槲皮素通过在Lys253处与C/EBPβ结合而抑制血管紧张素II诱导的腹主动脉瘤形成。因此,PMQ防止AAA的形成并降低AAA的发生率。
