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Published on: December 21, 2011
MiR-199a-5p-containing macrophage-derived extracellular vesicles inhibit SMARCA4 and alleviate atherosclerosis by
Weijie Liang1, Jun Chen1, Hongyan Zheng1
1Department of Cardiology, Cardiovascular Institute of Panyu District, Panyu Central Hospital, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China.
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 miR-199a-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-κB 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-κB axis, providing promising targets and strategies for the prevention and treatment of atherosclerosis.
Insights
Inhibition of miR-199a-5p in macrophage extracellular vesicles accelerates atherosclerosis by promoting endothelial cell pyroptosis via the SMARCA4/PODXL/NF-κB pathway. This finding offers potential therapeutic targets for atherosclerosis treatment.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- Endothelial cell dysfunction is central to atherosclerosis pathogenesis.
- MicroRNAs (miRs), particularly miR-199a-5p, are implicated in cardiovascular diseases, but their specific role in endothelial cells and atherosclerosis is unclear.
Purpose of the Study:
- To investigate the role of miR-199a-5p in endothelial cell phenotypes and atherosclerosis.
- To elucidate the mechanism by which miR-199a-5p influences atherosclerosis progression.
Main Methods:
- Atherosclerosis was induced in ApoE knockout mice fed a high-fat diet.
- Extracellular vesicles (EVs) from oxidized LDL-treated macrophages were isolated and co-cultured with human aortic endothelial cells (HAECs).
- miR-199a-5p levels were manipulated in EVs, and its effect on HAEC pyroptosis, LDH activity, and the SMARCA4/PODXL/NF-κB axis was assessed.
Main Results:
- Macrophage-derived EVs exacerbated inflammation and aortic plaque area in mice.
- miR-199a-5p expression was reduced in EVs from oxidized LDL-treated macrophages, and its inhibition promoted HAEC pyroptosis and LDH release.
- miR-199a-5p directly targeted SMARCA4, inhibiting its activation of the NF-κB pathway via PODXL upregulation in HAECs.
Conclusions:
- Inhibited miR-199a-5p packaged within macrophage EVs accelerates endothelial cell pyroptosis and atherosclerosis.
- The SMARCA4/PODXL/NF-κB signaling axis mediates this process.
- EV-packaged miR-199a-5p represents a potential therapeutic target for atherosclerosis.
