State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, No.5 Dong Dan San Tiao, Beijing 100005, China.
State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College, No.5 Dong Dan San Tiao, Beijing 100005, China.
J Genet Genomics. 2018 Jan 20;45(1):25-32. doi: 10.1016/j.jgg.2018.01.002. Epub 2018 Jan 17.
Abdominal aortic aneurysm (AAA) is a vascular degenerative disease. Macrophage polarization and the balance between classically activated macrophages (M1) and alternatively activated macrophages (M2) are crucial for AAA pathogenesis. The present study aims to investigate the roles of macrophage SIRT1 in AAA formation and macrophage polarization. We found that in mouse peritoneal macrophages, SIRT1 expression was decreased after M1 stimulation, but was enhanced after M2 stimulation. Results from SIRT1 mice and macrophage specific SIRT1 knockout mice with treatment of angiotensin II (Ang II) for 4 weeks showed that macrophage specific deficiency of SIRT1 increased the incidence of AAA and exacerbated the severity, including more severe aneurysm types, enlarged diameter of the aneurysm and increased degradation of elastin. In mouse aortas, SIRT1 deficiency increased the pro-inflammatory M1 molecule inducible nitric oxide synthase (iNOS), and decreased M2 molecules such as arginase 1 (Arg1) and mannose receptor (MR). Furthermore, in peritoneal macrophages, SIRT1 deficiency increased the expression of M1 inflammatory molecules, but decreased the expression of M2 molecules. Overexpression of SIRT1 had the opposite effects. Thus, macrophage specific knockout of SIRT1 influences macrophage polarization and accelerates Ang II-induced AAA formation.
腹主动脉瘤（AAA）是一种血管退行性疾病。巨噬细胞极化和经典激活型巨噬细胞（M1）与选择性激活型巨噬细胞（M2）之间的平衡对于 AAA 的发病机制至关重要。本研究旨在探讨巨噬细胞 SIRT1 在 AAA 形成和巨噬细胞极化中的作用。我们发现，在小鼠腹腔巨噬细胞中，M1 刺激后 SIRT1 表达减少，但 M2 刺激后 SIRT1 表达增强。用血管紧张素 II（Ang II）处理 4 周的 SIRT1 敲除小鼠和巨噬细胞特异性 SIRT1 敲除小鼠的结果表明，巨噬细胞特异性 SIRT1 缺失增加了 AAA 的发生率并加重了其严重程度，包括更严重的动脉瘤类型、更大的动脉瘤直径和弹性蛋白降解增加。在小鼠主动脉中，SIRT1 缺失增加了促炎 M1 诱导型一氧化氮合酶（iNOS），并降低了 M2 分子如精氨酸酶 1（Arg1）和甘露糖受体（MR）的表达。此外，在腹腔巨噬细胞中，SIRT1 缺失增加了 M1 炎性分子的表达，但降低了 M2 分子的表达。SIRT1 的过表达则具有相反的效果。因此，巨噬细胞特异性 SIRT1 缺失影响巨噬细胞极化并加速 Ang II 诱导的 AAA 形成。
