Peperomin E (PepE) protects against high fat diet-induced atherosclerosis in Apolipoprotein E deficient (ApoE-/-) mice through reducing inflammation via the suppression of NLRP3 signaling pathway

Peperomin E (PepE) is a type of secolignan, a major component of the plant Peperomia dindygulensis. It has been shown to exert anti-inflammatory effects; however, the effects of PepE on human atherosclerosis remain unexplored. In the study, we investigated the role of PepE in high fat diet (HFD) induced atherosclerosis using apolipoprotein E defcient (ApoE(-/-) ) mice. Elevated serum homocyteine, cholesterol, and triglyceride levels, accelerated progression of atherosclerosis and exacerbated macrophage infiltration into atherosclerotic lesions were observed in HFD-fed ApoE(-/-) mice, which were attenuated by PepE treatment. ApoE(-/-) mice fed with HFD exhibited significantly high levels of inflammation-associated regulators in artery tissues, accompanied with an increased expression of p-inhibitor of kappa Beta alpha (I kappa B alpha) and p-nuclear factor-kappa B (NF-kappa B), and the process was blocked by PepE administration. Further, we found NOD-like receptor pyrin 3 (NLRP3) inflammasome activation in artery tissues of HFD-fed ApoE mice. In vitro, silencing NLRP3 using small interfering RNA efficiently inhibited oxidized-low-density lipoprotein (oxLDL)-induced ASC and Caspase-1 expressions, interleukin (IL)-1 beta and IL-18 production in human aortic endothelial cells (HAECs). Further experiments indicated that NLRP3-ASC pathway was activated by reactive oxygen species (ROS), since ROS scavenger of N-acetylcysteine (NAC) prevented, which was further reduced by PepE addition. However, the anti-inflammatory effects of PepE on oxLDL-incubated HAECs were abolished by over-expression NLRP3. Together, our study revealed that PepE inhibited atherosclerosis development in HFD-fed ApoE (-/-) mice by suppressing NLRP3 inflammatory signaling pathway, and suggested that PepE might be a potential therapeutic strategy in the prevention of atherosclerosis.