MiR-199a-5p-containing macrophage-derived extracellular vesicles inhibit SMARCA4 and alleviate atherosclerosis by reducing endothelial cell pyroptosis,Cell Biology and Toxicology

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MiR-199a-5p-containing macrophage-derived extracellular vesicles inhibit SMARCA4 and alleviate atherosclerosis by reducing endothelial cell pyroptosis
Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2022-08-05 , DOI: 10.1007/s10565-022-09732-2
Weijie Liang ₁ , Jun Chen ₁ , Hongyan Zheng ₁ , Aiwen Lin ₁ , Jianhao Li ₁ , Wen Wu ₂ , Qiang Jie ₁

Affiliation

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.

Graphical abstract

中文翻译：

含有 MiR-199a-5p 的巨噬细胞来源的细胞外囊泡抑制 SMARCA4，通过减少内皮细胞焦亡来减轻动脉粥样硬化

背景

内皮细胞紊乱在动脉粥样硬化的发病机制中发挥着重要作用。值得注意的是，越来越多的研究表明 microRNA (miR) 在动脉粥样硬化中发挥着重要作用，并且 miR-199a-5p 失调与动脉粥样硬化和其他心血管疾病相关。然而，miR-199a-5p对内皮细胞表型和动脉粥样硬化的影响仍然很大程度上未知。

方法

ApoE ^-/−雄性小鼠喂食高脂肪饮食以检测炎症和主动脉斑块面积。从经过氧化低密度脂蛋白处理的 THP-1 衍生巨噬细胞 (THP-1-DM) 中分离出细胞外囊泡 (EV)，然后与人主动脉内皮细胞 (HAEC) 共培养。在 THP-1-DM 衍生的 EV 中进行 miR-199a-5p 的异位表达和下调，以评估 HAEC 的焦亡和乳酸脱氢酶 (LDH)。通过荧光素酶活性测定评估miR-199a-5p和SMARCA4之间的结合关系。

结果

ox-LDL 诱导的 THP-1-DM 衍生的 EV 可加速动脉粥样硬化小鼠的炎症和主动脉斑块面积。此外，ox-LDL诱导的THP-1-DM的EV中miR-199a-5p表达降低，并且miR-199a-5p抑制促进HAEC焦亡和LDH活性。此外，miR-199a-5p靶向并限制SMARCA4，然后SMARCA4通过增加HAEC中PODXL的表达来激活NF-κB通路。