Macrophage polarization is of great importance in the formation of atherosclerotic plaque. Homeobox A5 (HOXA5), one of the homeobox transcription factors, has been revealed to be closely associated with macrophage phenotype switching. This study aims to investigate the role of HOXA5 in carotid atherosclerosis (CAS). Herein, the role of HOXA5 was explored in polarized RAW264.7 macrophages in vitro and ApoE^−/− mice in vivo. Interestingly, compared with that in M0 macrophages, both the mRNA and protein expression levels of HOXA5 were decreased in lipopolysaccharide (LPS)/interferon (IFN)-γ-induced M1 macrophages, while increased in IL-4-induced M2 macrophages. In addition, in the presence of IL-4, HOXA5-overexpressing RAW264.7 cells preferred to polarizing toward M2 phenotypes. Furthermore, we found that HOXA5 bound to the promoter region and activated the expression of mediator subunit 1 (MED1), a gene known to regulate macrophage differentiation. Knocking MED1 down inhibited HOXA5-enhanced M2 macrophage polarization. In vivo, the CAS model was induced in ApoE^−/− mouse fed with a Western-type diet and placed a perivascular carotid collar. Decreased mRNA and protein expressions of HOXA5 were observed in carotid arteries of CAS mice. Forced overexpression of HOXA5 reduced intimal hyperplasia and lipid accumulation in carotid vessels, and it also promoted the polarization of macrophages to M2 subtypes. The expression of MED1 was decreased in atherosclerotic carotid vessels, while HOXA5 overexpression restored its change. Collectively, HOXA5 in carotid arteries is involved in the macrophage M1/M2 switching in atherosclerotic plaque, which may be associated with its transcriptional regulation of MED1.

中文翻译：

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HOXA5通过激活MED1诱导M2巨噬细胞极化减轻颈动脉粥样硬化

巨噬细胞极化对动脉粥样硬化斑块的形成具有重要意义。同源框 A5 (HOXA5) 是同源框转录因子之一，已被发现与巨噬细胞表型转换密切相关。本研究旨在探讨 HOXA5 在颈动脉粥样硬化 (CAS) 中的作用。在此，研究了 HOXA5 在体外极化 RAW264.7 巨噬细胞和 ApoE 中的作用^-/-小鼠体内。有趣的是，与 M0 巨噬细胞相比，脂多糖 (LPS)/干扰素 (IFN)-γ 诱导的 M1 巨噬细胞中 HOXA5 的 mRNA 和蛋白表达水平均降低，而 IL-4 诱导的 M2 巨噬细胞中 HOXA5 的表达水平升高。此外，在 IL-4 存在的情况下，过表达 HOXA5 的 RAW264.7 细胞更倾向于向 M2 表型极化。此外，我们发现 HOXA5 与启动子区域结合并激活介质亚基 1 (MED1) 的表达，MED1 是一种已知可调节巨噬细胞分化的基因。敲低 MED1 可抑制 HOXA5 增强的 M2 巨噬细胞极化。在体内，在 ApoE 中诱导 CAS 模型^-/-小鼠喂食西式饮食，并在血管周围放置颈动脉项圈。在 CAS 小鼠的颈动脉中观察到 HOXA5 的 mRNA 和蛋白表达降低。HOXA5 的强制过表达减少了颈动脉血管中的内膜增生和脂质积累，并且还促进了巨噬细胞向 M2 亚型的极化。动脉粥样硬化颈动脉血管中 MED1 的表达降低，而 HOXA5 过表达恢复了其变化。总的来说，颈动脉中的 HOXA5 参与了动脉粥样硬化斑块中巨噬细胞 M1/M2 的转换，这可能与其对 MED1 的转录调控有关。