Zhou Feng, Liu Dan, Ning Hao-feng, Yu Xiao-chen, Guan Xiu-ru
Laboratory Diagnostics Department, The Haerbin Medical University, 150001, China.
Laboratory Diagnostics Department, The Haerbin Medical University, 150001, China.
Biochem Biophys Res Commun. 2016 Apr 8;472(3):451-8. doi: 10.1016/j.bbrc.2016.01.065. Epub 2016 Feb 18.
Matrix metalloproteinase-9 (MMP-9) plays an important role in the remodeling of the extracellular matrix in atherosclerosis plaques. Autophagy protects macrophages against the processes of vascular disease. Our research explores how autophagy plays roles in macrophages to secret MMP-9.
In response to increased doses of oxLDL or CQ we monitored the autophagic flux. Our results revealed that oxLDL was dynamically associated with autophagy and 100 μg/ml oxLDL blocked autophagic flux in THP-1 cells. Moreover p62/SQSTM1 knocking down and CQ respectively inhibited and increased MMP-9 transcriptional expression. These effects were mediated by inhibition of NF-κB.
Abundant oxLDL blocked autophagic flux resulting in the aggregation of p62/SQSTM1. Then p62/SQSTM1 was involved in gene expression of MMP-9 via NF-κB-dependent signaling, and thus featuring novel plaque vulnerability properties of the atherosclerotic plaque. Understanding the mechanism that selectively modulates p62/SQSTM1 will provide a novel strategy for anti-atherogenesis.
基质金属蛋白酶-9（MMP-9）在动脉粥样硬化斑块的细胞外基质重塑中起重要作用。自噬可保护巨噬细胞免受血管疾病进程的影响。我们的研究探讨了自噬如何在巨噬细胞中发挥作用以分泌MMP-9。
针对增加剂量的氧化型低密度脂蛋白（oxLDL）或氯喹（CQ），我们监测了自噬通量。我们的结果显示，oxLDL与自噬动态相关，且100μg/ml的oxLDL阻断了THP-1细胞中的自噬通量。此外，p62/SQSTM1基因敲低和CQ分别抑制和增加了MMP-9的转录表达。这些效应是由核因子κB（NF-κB）的抑制介导的。
大量的oxLDL阻断了自噬通量，导致p62/SQSTM1聚集。然后，p62/SQSTM1通过NF-κB依赖的信号传导参与MMP-9的基因表达，从而表现出动脉粥样硬化斑块新的易损性特征。了解选择性调节p62/SQSTM1的机制将为抗动脉粥样硬化提供一种新策略。
