MicroRNA-30c-5p inhibits NLRP3 inflammasome-mediated endothelial cell pyroptosis through FOXO3 down-regulation in atherosclerosis
2018
Li, Peng | Zhong, Xiaoming | Li, Juan | Liu, Hongyang | Ma, Xiang | He, Ruili | Zhao, Yanzhuo
Atherosclerosis is a chronic inflammatory disease involved in endothelial dysfunction. Pyroptosis is a pro-inflammatory form of cell death and plays pivotal roles in atherosclerosis. MicroRNAs (miRNAs) are implicated in atherosclerosis, however the mechanisms that underlie miR-30c-5p is required for endothelial cell pyroptosis remain elusive. In the present study, we probed the interaction of miR-30c-5p with forkhead box O3 (FOXO3) and investigated the effect of miR-30c-5p and FOXO3 on NLRP3 inflammasome and endothelial cell pyroptosis. Introduction of oxidized low density lipoprotein (ox-LDL) dose-dependently increased lactate dehydrogenase (LDH) release as well as pyroptosis in human aortic endothelial cells (HAECs). On the basis of ox-LDL treatment, we found the expression of miR-30c-5p was impaired and enrichment of miR-30c-5p protected HAECs from ox-LDL-induced pyroptosis. Moreover, addition of miR-30c-5p inhibited ox-LDL-activated NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which was associated with HEACs pyroptosis. Nevertheless, miR-30c-5p failed to show efficacy of Toll-like receptor (TLR) signaling of NLRP3 inflammasome activation. Intriguingly, FOXO3 was suggested to be targeted by miR-30c-5p and addition of miR-30c-5p blocked FOXO3 expression, whereas miR-30c-5p depletion showed opposite effects. Furthermore, silencing of FOXO3 inhibited NLRP3-mediated pyroptosis and reversed anti-miR-30c-5p-induced activation of NLRP3 inflammasome and pyroptosis in HEACs with ox-LDL treatment. Our finding suggested that miR-30c-5p might play essential role in NLRP3 inflammasome-modulated cell pyroptosis by targeting FOXO3 in HAECs, providing a novel therapeutic avenue for atherosclerosis treatment.
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