Open AccessActivation of NLRP3 Inflammasome Promotes Foam Cell Formation in Vascular Smooth Muscle Cells and Atherogenesis Via HMGB1
Author(s) -
Wang Rui,
Wu Weibin,
Li Wen,
Huang Shuichuan,
Li Zilun,
Liu Ruiming,
Shan Zhen,
Zhang Chunxiang,
Li Wen,
Wang Shenming
Publication year - 2018
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.118.008596
Subject(s) - inflammasome , receptor , microbiology and biotechnology , foam cell , medicine , hmgb1 , biology , lipoprotein , cholesterol
Background This study aimed at investigating whether NLRP 3 (the Nod like receptor family, pyrin domain‐containing 3 protein) inflammasome activation induced HMGB 1 (high mobility group box‐1 protein) secretion and foam cell formation in human vascular smooth muscle cells ( VSMC s) and atherosclerosis in ApoE −/− mice. Methods and Results VSMC s or ApoE −/− mice were treated with lipopolysaccharides ( LPS ) and/or ATP or LPS and high‐fat diet to induce NLRP 3 inflammasome activation. HMGB 1 distribution and foam cell formation in VSMC s were characterized. Liver X receptor α and ATP ‐binding cassette transporter expression were determined. The impact of NLRP 3 or receptor for advanced glycation end product silencing, ZYVAD ‐ FMK (caspase‐1 inhibitor), glycyrrhizin ( HMGB 1 inhibitor) or receptor for advanced glycation end product antagonist peptide on HMGB 1 secretion, foam cell formation, liver X receptor α and ATP ‐binding cassette transporter expression was examined. Expression level of HMGB 1 in human atherosclerosis obliterans arterial tissues was characterized. Our results found that NLRP 3 inflammasome activation promoted foam cell formation and HMGB 1 secretion in VSMC s. Extracellular HMGB 1 was a key signal molecule in inflammasome activation‐mediated foam cell formation. Furthermore, inflammasome activation‐induced HMGB 1 activity and foam cell formation were achieved by receptor for advanced glycation end product/liver X receptor α / ATP ‐binding cassette transporter glycyrrhizin. Experiments in vivo found glycyrrhizin significantly attenuated the LPS /high‐fat diet‐induced atherosclerosis and serum HMGB 1 levels in mice. Finally, levels of HMGB 1 and NLRP 3 were increased in tunica media adjacent to intima of atherosclerosis obliteran arteries. Conclusions Our results revealed that HMGB1 is a key downstream signal molecule of NLRP 3 inflammasome activation and plays an important role in VSMC s foam cell formation and atherogenesis by downregulating liver X receptor α and ATP ‐binding cassette transporter expression through receptor for advanced glycation end product.