期刊
CELL BIOLOGY AND TOXICOLOGY
卷 39, 期 3, 页码 591-605出版社
SPRINGER
DOI: 10.1007/s10565-022-09732-2
关键词
Extracellular vesicles; Macrophage; miR-199a-5p; SMARCA4; PODXL; NF-kappa B pathway; Pyroptosis; Atherosclerosis
Studies suggest that EVs derived from ox-LDL-induced macrophages accelerate inflammation and plaque formation in atherosclerosis. Inhibition of miR-199a-5p promotes endothelial cell pyroptosis and LDH activity through the SMARCA4/PODXL/NF-kappa B pathway.
Background Endothelial cell disturbance underpins a role in pathogenesis of atherosclerosis. Notably, accumulating studies indicate the substantial role of microRNAs (miRs) in atherosclerosis, and miR-199a-5p dysregulation has been associated with atherosclerosis and other cardiovascular disorders. However, the effect of miR199a-5p on the phenotypes of endothelial cells and atherosclerosis remains largely unknown. Methods ApoE(-/-) male mice were fed with high-fat diet for detection of inflammation and aorta plaque area. Extracellular vesicles (EVs) were separated from THP-1-derived macrophage (THP-1-DM) that was treated by oxidized low-density lipoprotein, followed by co-culture with human aortic endothelial cells (HAECs). Ectopic expression and downregulation of miR-199a-5p were done in THP-1-DM-derived EVs to assess pyroptosis and lactate dehydrogenase (LDH) of HAECs. Binding relationship between miR-199a-5p and SMARCA4 was evaluated by luciferase activity assay. Results EVs derived from ox-LDL-induced THP-1-DM expedited inflammation and aorta plaque area in atherosclerotic mice. Besides, miR-199a-5p expression was reduced in EVs from ox-LDL-induced THP-1-DM, and miR-199a-5p inhibition facilitated HAEC pyroptosis and LDH activity. Moreover, miR-199a-5p targeted and restricted SMARCA4, and then SMARCA4 activated the NF-kappa B pathway by increasing PODXL expression in HAECs. Conclusion EV-packaged inhibited miR-199a-5p from macrophages expedites endothelial cell pyroptosis and further accelerates atherosclerosis through the SMARCA4/PODXL/NF-kappa B axis, providing promising targets and strategies for the prevention and treatment of atherosclerosis.
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