Inhibiting microRNA-200a-3p attenuates pyroptosis via targeting the SIRT1/NF-κB/NLRP3 pathway in HO-induced HAEC.

Atherosclerosis is a chronic inflammatory disease of the arterial wall caused by many factors. Endothelial cell dysfunction is the initial factor in the development of atherosclerosis, and ROS activates the assembly of inflammasomes and induces the pyroptosis of vascular endothelial cells. Whether HO induced human aortic endothelial cells (HAECs) pyroptosis and the underlying mechanisms remain unclear. This study aimed to investigate the role of microRNA-200a-3p in HO-induced HAECs pyroptosis. First, we found that the pyroptosis-related protein was upregulated in aortia in HFD mice. The study showed that the activation of NLRP3 inflammasomes and the pyroptosis in HO-induced HAECs, which is characterized by an increase in Lactate dehydrogenase (LDH) activity, and an increase in propidium iodide (PI)-positive cells. The expression of silent information regulator of transcription 1 (SIRT1) was also decreased in HO-induced HAECs, and the overexpression of SIRT1 could reverse the occurrence of pyroptosis, partly through p65 deacetylation, thereby inhibiting nuclear translocation of p65 and regulating NLRP3 expression. Further studies revealed increased miRNA-200a-3p expression in HO-induced HAECs and the promotion of pyroptosis, which was achieved by targeting SIRT1. Inhibition of miR-200a-3p reduced pyroptosis by promoting the expression of the downstream target gene SIRT1 and reducing the accumulation of p65 and NLRP3. Collectively, our results suggest that HO can regulate NLRP3 inflammasomes through the miR-200a-3p/SIRT1/NF-κB (p65) signaling pathway and promote HAEC pyroptosis. The miR-200a-3p inhibitor can promote the expression of SIRT1 and inhibit pyroptosis, which may be important to prevent and treat atherosclerosis.