PM2.5 induce the defective efferocytosis and promote atherosclerosis via HIF-1α activation in macrophage

Epidemiological studies demonstrate that fine particulate matter (PM_2.5) promotes the development of atherosclerosis. However, the mechanism insight of PM_2.5-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_2.5-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_2.5. Yet, knockout of HIF-1α markedly decreased the PM_2.5-triggered atherosclerotic lesion. We firstly performed microarray analysis in PM_2.5-treated bone morrow-derived macrophages (BMDMs), which showed that PM_2.5 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_2.5-induced defective efferocytosis. Mechanistically, PM_2.5 inhibited the level of genes and proteins of efferocytosis receptor c-Mer tyrosine kinase (MerTK), especially in VHL-null BMDMs. In addition, PM_2.5 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_2.5-exposed mice. Moreover, PM_2.5 could induce defective efferocytosis and activate inflammatory response through MerTK/IFNAR1/STAT1 signaling pathway in macrophages. Our results demonstrate that PM_2.5 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_2.5-related atherosclerosis.