ABSTRACT

Macrophage derived foam cells in atherosclerotic plaques are the major factor responsible for the pathogenesis of atherosclerosis (AS). During advanced AS, macrophage-specific macroautophagy/autophagy is dysfunctional. 1, 25-dihydroxy vitamin D3 (VitD3) and its receptor VDR (vitamin D receptor) are reported to inhibit foam cell formation and induce autophagy; however, the role of VitD3-VDR-induced autophagy and foam cell formation in AS has not been explored. Here we find that VitD3 significantly recovered oxidized low-density lipoprotein-impaired autophagy, as well as increased autophagy-mediated lipid breakdown in mouse bone marrow-derived macrophages and human monocyte-derived macrophages, thus inhibiting the conversion of macrophages into foam cells. Importantly, VitD3 functions through its receptor VDR to upregulate autophagy and attenuate the accumulation of lipids in macrophages. Moreover, this study is the first occasion to report the interesting link between VitD3 signaling and PTPN6/SHP-1 (protein tyrosine phosphatase non-receptor type 6) in macrophages. VitD3-induced autophagy was abrogated in the presence of the PTPN6/Ptpn6 shRNA or inhibitor. VDR along with RXRA (retinoid X receptor alpha), and NCOA1 (nuclear receptor coactivator 1), are recruited to a specific response element located on the gene promoter and induce PTPN6 expression. PTPN6 contributes to VitD3-mediated autophagy by regulating autophagy-related genes via activation of MAPK1 (mitogen-activated protein kinase 1) and CEBPB (CCAAT enhancer binding protein beta). Furthermore, expression of PTPN6 is also crucial for VitD3-mediated inhibition of macrophage foam cell formation through autophagy. Thus, VitD3-VDR-PTPN6 axis-regulated autophagy attenuates foam cell formation in macrophages.

摘要

动脉粥样硬化斑块中巨噬细胞衍生的泡沫细胞是导致动脉粥样硬化（AS）发病机制的主要因素。在晚期 AS 期间，巨噬细胞特异性巨自噬/自噬功能失调。1、25-二羟基维生素D3（VitD3）及其受体VDR（维生素D受体）据报道可抑制泡沫细胞形成并诱导自噬；然而，尚未探索 VitD3-VDR 诱导的自噬和泡沫细胞形成在 AS 中的作用。在这里，我们发现 VitD3 在小鼠骨髓来源的巨噬细胞和人单核细胞来源的巨噬细胞中显着恢复了氧化的低密度脂蛋白受损的自噬，并增加了自噬介导的脂质分解，从而抑制了巨噬细胞向泡沫细胞的转化。重要的，VitD3 通过其受体 VDR 上调自噬并减弱巨噬细胞中脂质的积累。此外，这项研究首次报道了巨噬细胞中 VitD3 信号传导与 PTPN6/SHP-1（蛋白酪氨酸磷酸酶非受体 6 型）之间的有趣联系。VitD3 诱导的自噬在存在PTPN6 / Ptpn6 shRNA 或抑制剂。VDR 与 RXRA（类维生素 X 受体 α）和 NCOA1（核受体共激活因子 1）一起被募集到位于基因启动子上的特定反应元件并诱导 PTPN6 表达。PTPN6 通过激活 MAPK1（丝裂原活化蛋白激酶 1）和 CEBPB（CCAAT 增强子结合蛋白 β）来调节自噬相关基因，从而促进 VitD3 介导的自噬。此外，PTPN6 的表达对于 VitD3 介导的通过自噬抑制巨噬细胞泡沫细胞形成也是至关重要的。因此，VitD3-VDR-PTPN6 轴调节的自噬减弱了巨噬细胞中泡沫细胞的形成。