Atherosclerosis (AS) is a multifactorial chronic inflammatory disease, and hyperlipidemia is the important factors leading to AS, which can cause vascular endothelial dysfunction. Paeonol (Pae) is a potential therapeutic drug for AS, and we have previously shown that Pae regulated the expression of monocytes-derived exosomal microRNA-223 (miR-223). However, the mechanisms of the anti-AS effect of Pae are still not fully understood. In this study, we aim to investigate if Pae could inhibit NLRP3 inflammasome mediated inflammation via elevating hyperlipidemic rats plasma-derived exosomal miR-223. We used high-fat-diet induced hyperlipidemic rats as model for further investigation. Rats were treated with Pae (75, 150 or 300 mg/kg) orally, and then exosomes were isolated from hyperlipidemic rat plasma by ultracentrifugation. In vivo experiments confirmed that Pae markedly reduced serum TC, TG, IL-1β, and IL-6 levels. Both CCK-8 and trypan blue staining showed that the survival rate of rat aortic endothelial cells (RAECs) in the Pae-exo group was higher than that in the model group. Also, Pae-exo dose-dependently increased the survival rate of RAECs and reduced inflammatory cytokines level (IL-1β, and IL-6). Furthermore, Pae-exo successfully increased the expression of exosomal miR-223 and relieved inflammatory secretion. Finally, decreased expression of NLRP3, ASC, caspase-1 and ICAM-1 indicated that Pae-exo attenuated inflammatory reaction of RAECs by suppressing NLRP3 signaling pathway. Altogether, our results showed that Pae inhibited the downstream NLRP3 inflammasome pathway by increasing the level of miR-223 in plasma derived exosomes of hyperlipidemic rats, providing new insights in the treatment of AS with the use of Pae.
Keywords: Exosomes; Hyperlipidemia; NLRP3; Paeonol; RAECs; miR-223.
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