Rutaecarpine derivative R3 attenuates atherosclerosis via inhibiting NLRP3 inflammasome‐related inflammation and modulating cholesterol transport

Abstract Atherosclerosis is a chronic disease characterized by lipid deposition and inflammatory response. NOD‐, LRR‐ and pyrin domain‐containing protein 3 (NLRP3) inflammasome‐facilitated inflammatory responses are crucial in the pathogenesis of atherosclerosis, and thus new therapeutic approaches are emerging that target NLRP3 and inflammation. Here, we explored the anti‐atherosclerotic effect and mechanisms of a new rutaecarpine derivative, 5‐deoxy‐rutaecarpine (R3) in vitro and in vivo. R3 treatment attenuated atherosclerosis development and increased plaque stability in Apoe −/− mice fed a high‐fat diet, and decreased levels of inflammatory mediators, such as interleukin‐1β, in the serum of Apoe −/− mice and in oxidized low‐density lipoprotein (ox‐LDL)‐stimulated murine macrophages. R3 treatment inhibited NLRP3 inflammasome activation in the livers of Apoe −/− mice and ox‐LDL‐stimulated murine macrophages by inhibiting NF‐κB and MAPK pathways. Additionally, R3 significantly decreased total cholesterol in the serum and livers of Apoe −/− mice and promoted cholesterol efflux in murine macrophages through upregulating protein expression of ATP‐binding cassette subfamily A member 1 and scavenger receptor class B type I/human CD36 and lysosomal integral membrane protein‐II analogous‐1. Our results demonstrated that R3 prevented atherosclerotic progression via attenuating NLRP3 inflammasome‐related inflammation and modulating cholesterol transport.