Macrophage migration is thought to participate in obesity‐related cardiovascular diseases. Matrix metalloproteinase‐8 (MMP‐8) possesses proteolytic activity on the extracellular matrix (ECM), which promotes macrophage migration to the site of vascular injury. Neuropeptide Y (NPY) is a bioactive peptide involved in MMP expression. However, it is uncertain whether NPY can regulate the expression of matrix metalloproteinase‐8 (MMP‐8) in macrophages. In this study, wild‐type C57BL/6 and NPY^−/− mice were fed a high‐fat diet and subjected to subcutaneous carotid artery injury with ferric chloride, to observe the role of NPY and macrophages in neointima formation. In addition, Raw264.7 cells were treated with NPY and its antagonists to observe MMP‐8 expression and macrophage migration. We found that NPY^−/− mice exhibited significantly reduced neointima formation after carotid artery injury. The content of macrophages and MMP‐8 in the neointima and media were also significantly reduced in NPY^−/− mice compared with C57BL/6 mice. Moreover, the expression of MMP‐8 in macrophages was also decreased in NPY^−/− mice. NPY increased MMP‐8 messenger RNA and protein expression in Raw264.7 cells in vitro, and this effect was abrogated by the Y1R antagonist. In addition, NPY increased the phosphorylation of ERK1/2, which was significantly attenuated by co‐treatment with the Y1R antagonist. Moreover, NPY‐induced MMP‐8 expression could be decreased by the ERK1/2 inhibitor PD98059. Furthermore, NPY promoted macrophage migration across type I collagen in vitro. In conclusion, NPY promotes macrophage migration by upregulating MMP‐8 expression, which we believe to be an underappreciated mechanism of the increased progression of neointima formation.

中文翻译：

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NPY 通过上调基质金属蛋白酶 8 的表达来促进巨噬细胞迁移。

巨噬细胞迁移被认为与肥胖相关的心血管疾病有关。基质金属蛋白酶-8 (MMP-8) 对细胞外基质 (ECM) 具有蛋白水解活性，可促进巨噬细胞迁移至血管损伤部位。神经肽 Y (NPY) 是一种参与 MMP 表达的生物活性肽。然而，NPY是否可以调节巨噬细胞中基质金属蛋白酶8（MMP-8）的表达尚不确定。在这项研究中，野生型 C57BL/6 和 NPY ^-/-小鼠被喂食高脂饮食并用氯化铁进行皮下颈动脉损伤，以观察 NPY 和巨噬细胞在新内膜形成中的作用。此外，用 NPY 及其拮抗剂处理 Raw264.7 细胞以观察 MMP-8 表达和巨噬细胞迁移。我们发现 NPY^-/-小鼠在颈动脉损伤后表现出显着减少的新内膜形成。与 C57BL/6 小鼠相比，NPY ^-/-小鼠新内膜和中膜中巨噬细胞和 MMP-8 的含量也显着降低。此外，巨噬细胞中 MMP-8 的表达在 NPY ^{-/- 中}也降低老鼠。NPY 在体外增加了 Raw264.7 细胞中 MMP-8 信使 RNA 和蛋白质的表达，而这种作用被 Y1R 拮抗剂消除。此外，NPY 增加了 ERK1/2 的磷酸化，这通过与 Y1R 拮抗剂的共同处理而显着减弱。此外，ERK1/2抑制剂PD98059可以降低NPY诱导的MMP-8表达。此外，NPY 在体外促进巨噬细胞跨 I 型胶原的迁移。总之，NPY 通过上调 MMP-8 表达来促进巨噬细胞迁移，我们认为这是新内膜形成进展增加的一种被低估的机制。