Department of Cardiovascular Medicine, Weifang People's Hospital, Weifang, Shandong Province, 261041, China.
Department of Cardiovascular Medicine, Weifang People's Hospital, Weifang, Shandong Province, 261041, China.
Biochem Biophys Res Commun. 2021 Mar 5;543:29-37. doi: 10.1016/j.bbrc.2020.09.132. Epub 2021 Jan 25.
Pregnancy-associated plasma protein-A (PAPP-A), a type of metalloproteinase in the insulin-like growth factor (IGF) system, has been implicated in atherosclerosis progression, but its function and mechanism in atherosclerosis is not fully understood. The study was performed to further explore the effects of PAPP-A on inflammation, macrophage polarization and atherosclerosis. In mouse macrophages stimulated by oxidized low-density lipoprotein (ox-LDL), PAPP-A expression was significantly increased. Its knockdown markedly mitigated inflammatory response and polarized macrophages to an M2-like phenotype in RAW264.7 cells upon ox-LDL treatment. Additionally, ox-LDL-induced activation of nuclear factor-κB (NF-κB) signaling pathway was dramatically restricted by PAPP-A knockdown in macrophages. However, JAK2/STAT3 activation was significantly up-regulated in RAW264.7 cells with PAPP-A inhibition after ox-LDL treatment. Importantly, we found that PAPP-A knockdown-induced polarization of M2-like phenotype in macrophages was mainly dependent on STAT3 activation. Clinical studies showed that serum PAPP-A levels were higher in patients with coronary artery disease (CAD) than that of healthy individuals. Apolipoprotein E-knockout (ApoE) mice with high fat diet (HFD)-induced atherosclerosis exhibited higher expression of PAPP-A in aortas, which was mainly colocalized with F4/80. Subsequently, we found that PAPP-A deficiency greatly alleviated plaque formation, lesion burden and collagen accumulation in HFD-fed ApoE mice. Consistent with in vitro macrophage phenotype, PAPP-A reduced F4/80 expression, NF-κB activation and inflammatory response, while improved janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling and polarized macrophages to an M2-like phenotype in aortas of ApoE mice after HFD feeding. In conclusion, these findings identified PAPP-A as a positive regulator of atherosclerosis by regulating macrophage polarization via STAT3 signal, and thus could be considered as a potential therapeutic target for atherosclerosis treatment.
妊娠相关血浆蛋白 A（PAPP-A）是胰岛素样生长因子（IGF）系统中的一种金属蛋白酶，与动脉粥样硬化进展有关，但它在动脉粥样硬化中的功能和机制尚未完全阐明。本研究旨在进一步探讨 PAPP-A 对炎症、巨噬细胞极化和动脉粥样硬化的影响。在氧化低密度脂蛋白（ox-LDL）刺激的小鼠巨噬细胞中，PAPP-A 表达明显增加。在 RAW264.7 细胞中，PAPP-A 敲低显著减轻了 ox-LDL 处理后的炎症反应，并使巨噬细胞向 M2 样表型极化。此外，ox-LDL 诱导的核因子-κB（NF-κB）信号通路的激活在巨噬细胞中被 PAPP-A 敲低显著抑制。然而，在 ox-LDL 处理后，RAW264.7 细胞中 JAK2/STAT3 的激活明显上调。重要的是，我们发现 PAPP-A 敲低诱导的巨噬细胞 M2 样表型极化主要依赖于 STAT3 的激活。临床研究表明，冠心病（CAD）患者的血清 PAPP-A 水平高于健康个体。高脂饮食（HFD）诱导动脉粥样硬化的载脂蛋白 E 敲除（ApoE）小鼠主动脉中 PAPP-A 表达升高，主要与 F4/80 共定位。随后，我们发现 PAPP-A 缺乏可显著减轻 HFD 喂养的 ApoE 小鼠斑块形成、病变负荷和胶原积累。与体外巨噬细胞表型一致，PAPP-A 降低了 F4/80 表达、NF-κB 激活和炎症反应，同时改善了 JAK2/STAT3 信号，并使 HFD 喂养的 ApoE 小鼠主动脉中的巨噬细胞向 M2 样表型极化。总之，这些发现确定了 PAPP-A 通过 STAT3 信号调节巨噬细胞极化作为动脉粥样硬化的正调节剂，因此可以被认为是动脉粥样硬化治疗的潜在治疗靶点。
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