Cheng Shaopeng, Wang Yilin, Tong Tingting, Liu Chen, Qian Jintao, Zong Qiuyan, Wang Dongjin, Li Kai, Wu Xiaoting, Yang Jie
Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, PR China; Institute of Cardiothoracic Vascular Disease, Nanjing University, Nanjing, Jiangsu, PR China.
Institute of Cardiothoracic Vascular Disease, Nanjing University, Nanjing, Jiangsu, PR China; Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, PR China.
Phytomedicine. 2025 Oct;146:157101. doi: 10.1016/j.phymed.2025.157101. Epub 2025 Jul 23.
Abdominal aortic aneurysm (AAA) is a lethal vascular disorder characterized by aortic dilation and medial degeneration, with no effective pharmacological interventions currently available. Pathological vascular smooth muscle cell (VSMC) phenotypic switching and apoptosis drive AAA progression. Mangiferin, a bioactive xanthone from Mangiferia indica l., exhibits anti-inflammatory and cardiovascular protective properties that could potentially alleviate AAA.
This study aims to investigate mangiferin's therapeutic effects on AAA and elucidate its molecular mechanisms.
Apolipoprotein E-deficient (ApoE) mice were infused with angiotensin II (Ang II) to induce AAA and subsequently treated with low-dose (10 mg/kg/d) or high-dose (50 mg/kg/d) mangiferin. Aortic pathology was assessed via histological analysis, zymography, and immunofluorescence. VSMC phenotypic switching and apoptosis were examined through western blotting and immunofluorescence, while their molecular regulation by mangiferin was investigated using a combined approach of RNA-sequencing, molecular docking, cellular thermal shift assay, and functional studies.
Compared to low dose-mangiferin, high dose-mangiferin reduced the incidence of AAA, aneurysm diameter enlargement, and elastin degradation in the AAA model. Mangiferin pretreatment also attenuated VSMC phenotypic switching and apoptosis in Ang II-stimulated VSMCs compared to non-pretreatment. Mechanistically, mangiferin directly bound to STAT3 at Lys591 via hydrogen bonding in the SH2 domain, inhibiting its Tyr705 phosphorylation and dimerization, and eventually blocking its nuclear translocation. This in turn suppressed KLF5 transcriptional activity and pro-aneurysmal target expression. Furthermore, both pharmacological and genetic activation of the STAT3-KLF5 axis abrogated mangiferin's protective effects in the AAA model.
This study is the first to demonstrate that mangiferin inhibits AAA by targeting the STAT3-KLF5 axis to stabilize VSMC contractility and survival, placing mangiferin as a novel natural therapeutic candidate for AAA.
腹主动脉瘤（AAA）是一种致命的血管疾病，其特征为主动脉扩张和中膜退变，目前尚无有效的药物干预措施。病理性血管平滑肌细胞（VSMC）表型转换和凋亡推动AAA进展。芒果苷是一种从芒果中提取的生物活性呫吨酮，具有抗炎和心血管保护特性，可能缓解AAA。
本研究旨在探讨芒果苷对AAA的治疗作用并阐明其分子机制。
给载脂蛋白E缺陷（ApoE）小鼠输注血管紧张素II（Ang II）以诱导AAA，随后用低剂量（10 mg/kg/d）或高剂量（50 mg/kg/d）芒果苷进行治疗。通过组织学分析、酶谱分析和免疫荧光评估主动脉病理。通过蛋白质印迹和免疫荧光检测VSMC表型转换和凋亡，同时使用RNA测序、分子对接、细胞热位移分析和功能研究相结合的方法研究芒果苷对其的分子调控。
与低剂量芒果苷相比，高剂量芒果苷降低了AAA模型中AAA的发生率、动脉瘤直径扩大和弹性蛋白降解。与未预处理相比，芒果苷预处理还减轻了Ang II刺激的VSMC中的VSMC表型转换和凋亡。机制上，芒果苷通过SH2结构域中的氢键直接与STAT3的Lys591结合，抑制其Tyr705磷酸化和二聚化，并最终阻止其核转位。这进而抑制了KLF5转录活性和促动脉瘤靶标表达。此外，STAT3-KLF5轴的药理学和基因激活均消除了芒果苷在AAA模型中的保护作用。
本研究首次证明芒果苷通过靶向STAT3-KLF5轴抑制AAA，以稳定VSMC收缩性和存活，使芒果苷成为AAA的新型天然治疗候选物。
