Institute of Cardiothoracic Vascular Disease, Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
Institute of Cardiothoracic Vascular Disease, Department of Cardio-Thoracic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
Biochem Pharmacol. 2024 May;223:116170. doi: 10.1016/j.bcp.2024.116170. Epub 2024 Mar 26.
Aortic Aneurysm and Dissection (AAD) are severe cardiovascular conditions with potentially lethal consequences such as aortic rupture. Existing studies suggest that liraglutide, a long-acting glucagon-like peptide receptor (GLP-1R) agonist, offers protective benefits across various cardiovascular diseases. However, the efficacy of liraglutide in mitigating AAD development is yet to be definitively elucidated.
Ang II (Angiotension II) infusion of APOE mouse model with intraperitoneal injection of liraglutide (200 μg/kg) to study the role of GLP-1R in AAD formation. Bone Marrow Derived Macrophages (BMDM) and Raw264.7 were incubated with LPS, liraglutide, exendin 9-39 or LY294002 alone or in combination. SMC phenotype switching was examined in a macrophage and vascular smooth muscle cell (VSMC) co-culture system. An array of analytical methods, including Western Blot, Immunofluorescence Staining, Enzyme-LinkedImmunosorbent Assay, Real-Time Quantitative Polymerase Chain Reaction, RNA-seq, and so on were employed.
Our investigation revealed a significant increase in M1 macrophage polarization and GLP-1R expression in aortas of AD patients and Ang II-induced AAD APOE mice. Administering liraglutide in APOE mice notably reduced Ang II-induced AAD incidence and mortality. It was found that liraglutide inhibits M1 macrophage polarization primarily via GLP-1R activation, and subsequently modulates vascular smooth muscle cell phenotypic switching was the primary mechanism. RNA-Seq and subsequent KEGG enrichment analysis identified CXCL3, regulated by the PI3K/AKT signaling pathway, as a key element in liraglutide's modulation of M1 macrophage polarization.
Our study found liraglutide exhibits protective effects against AAD by modulating M1 macrophage polarization, suppressing CXCL3 expression through the PI3K/AKT signaling pathway. This makes it a promising therapeutic target for AAD, offering a new avenue in AAD management.
主动脉瘤和夹层（AAD）是严重的心血管疾病，可能导致主动脉破裂等致命后果。现有研究表明，利拉鲁肽是一种长效胰高血糖素样肽受体（GLP-1R）激动剂，对多种心血管疾病具有保护作用。然而，利拉鲁肽在减轻 AAD 发展方面的疗效尚未得到明确证实。
采用血管紧张素 II（Ang II）输注 APOE 小鼠模型，腹腔内注射利拉鲁肽（200μg/kg），研究 GLP-1R 在 AAD 形成中的作用。将骨髓来源的巨噬细胞（BMDM）和 Raw264.7 与 LPS、利拉鲁肽、Exendin 9-39 或 LY294002 单独或联合孵育。在巨噬细胞和血管平滑肌细胞（VSMC）共培养系统中检测 SMC 表型转换。采用 Western Blot、免疫荧光染色、酶联免疫吸附试验、实时定量聚合酶链反应、RNA-seq 等多种分析方法。
我们的研究发现，AD 患者和 Ang II 诱导的 AAD APOE 小鼠的主动脉中 M1 巨噬细胞极化和 GLP-1R 表达显著增加。在 APOE 小鼠中给予利拉鲁肽可显著降低 Ang II 诱导的 AAD 发生率和死亡率。结果表明，利拉鲁肽主要通过 GLP-1R 激活抑制 M1 巨噬细胞极化，进而调节血管平滑肌细胞表型转换是其主要机制。RNA-seq 和随后的 KEGG 富集分析发现，CXCL3 是 PI3K/AKT 信号通路调节的关键元素，在利拉鲁肽调节 M1 巨噬细胞极化中起关键作用。
本研究发现，利拉鲁肽通过调节 M1 巨噬细胞极化对 AAD 发挥保护作用，通过 PI3K/AKT 信号通路抑制 CXCL3 表达。这使其成为 AAD 的一种有前途的治疗靶点，为 AAD 的治疗提供了新的途径。
