期刊
FASEB JOURNAL
卷 34, 期 1, 页码 1398-1411出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201900903RRR
关键词
ABCA1; IL-1 beta; macrophage; MAPK; NF-kappa B
资金
- National Natural Science Foundation of China (NSFC) [81573482, 81621064, 81973328]
- National Science and Technology Major Project of the Ministry of Science and Technology of China [2018ZX09711001003-006, 2018ZX09711001-007-002, 2018ZX09735001-001-002]
- CAMS Fundamental Research Funds [2019-RC-HL-009]
- CAMS Innovation Fund for Medical Sciences [2016-I2M-1-011]
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-1 beta, 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-kappa B 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.
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