Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, P.R. China.
Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, P.R. China.
Nanotoxicology. 2022 Apr;16(3):290-309. doi: 10.1080/17435390.2022.2083995. Epub 2022 Jun 2.
Epidemiological studies demonstrate that fine particulate matter (PM) promotes the development of atherosclerosis. However, the mechanism insight of PM-induced atherosclerosis is still lacking. The aim of this study was to explore the biological effects of hypoxia-inducible factor 1α (HIF-1α) on PM-triggered atherosclerosis. The vascular stiffness, carotid intima-media thickness (CIMT), lipid and atherosclerotic lesion were increased when von Hippel-Lindau (VHL)-null mice were exposed to PM. Yet, knockout of HIF-1α markedly decreased the PM-triggered atherosclerotic lesion. We firstly performed microarray analysis in PM-treated bone morrow-derived macrophages (BMDMs), which showed that PM significantly changed the genes expression patterns and affected biological processes such as phagocytosis, apoptotic cell clearance, cellular response to hypoxia, apoptotic process and inflammatory response. Moreover, the data showed knockout of HIF-1α remarkably relieved PM-induced defective efferocytosis. Mechanistically, PM inhibited the level of genes and proteins of efferocytosis receptor c-Mer tyrosine kinase (MerTK), especially in VHL-null BMDMs. In addition, PM increased the genes and proteins of a disintegrin and metallopeptidase domain 17 (ADAM17), which caused the MerTK cleavage to form soluble MerTK (sMer) in plasma and cellular supernatant. The sMer was significantly up-regulated in plasma of VHL-null PM-exposed mice. Moreover, PM could induce defective efferocytosis and activate inflammatory response through MerTK/IFNAR1/STAT1 signaling pathway in macrophages. Our results demonstrate that PM could induce defective efferocytosis and inflammation by activating HIF-1α in macrophages, ultimately resulting in accelerating atherosclerotic lesion formation and development. Our data suggest HIF-1α in macrophages might be a potential target for PM-related atherosclerosis.
流行病学研究表明，细颗粒物（PM）可促进动脉粥样硬化的发生。然而，PM 诱导动脉粥样硬化的确切机制仍不清楚。本研究旨在探讨低氧诱导因子 1α（HIF-1α）在 PM 引发动脉粥样硬化中的生物学作用。当 von Hippel-Lindau（VHL）缺陷型小鼠暴露于 PM 时，血管僵硬、颈动脉内膜中层厚度（CIMT）、脂质和动脉粥样硬化病变增加，而 HIF-1α 敲除则显著减少了 PM 引发的动脉粥样硬化病变。我们首先对 PM 处理的骨髓源性巨噬细胞（BMDMs）进行了基因芯片分析，结果显示 PM 显著改变了基因表达模式，并影响了吞噬作用、凋亡细胞清除、细胞对缺氧的反应、凋亡过程和炎症反应等生物学过程。此外，数据显示 HIF-1α 敲除显著缓解了 PM 诱导的吞噬作用缺陷。机制上，PM 抑制了吞噬作用受体 c-Mer 酪氨酸激酶（MerTK）的基因和蛋白水平，特别是在 VHL 缺陷型 BMDMs 中。此外，PM 增加了 a 型血小板反应蛋白 17 （ADAM17）的基因和蛋白水平，导致 MerTK 裂解形成可溶性 MerTK（sMer）在血浆和细胞上清液中。VHL 缺陷型 PM 暴露小鼠的血浆中 sMer 明显上调。此外，PM 可以通过巨噬细胞中的 MerTK/IFNAR1/STAT1 信号通路诱导吞噬作用缺陷和激活炎症反应。我们的结果表明，PM 可通过激活巨噬细胞中的 HIF-1α 诱导吞噬作用缺陷和炎症反应，从而加速动脉粥样硬化病变的形成和发展。我们的数据表明，巨噬细胞中的 HIF-1α 可能是 PM 相关动脉粥样硬化的一个潜在靶点。
