Activation of NLRP3 Inflammasome Promotes Foam Cell Formation in Vascular Smooth Muscle Cells and Atherogenesis Via HMGB1

作者：Wang, Rui; Wu, Weibin; Li, Wen; Huang, Shuichuan; Li, Zilun; Liu, Ruiming; Shan, Zhen; Zhang, Chunxiang; Li, Wen; Wang, Shenming^*

来源：Journal of the American Heart Association, 2018, 7(19): e008596.

DOI：10.1161/JAHA.118.008596

• ATP-binding cassette transporter
• foam cells
• Lipid metabolites
• Nod like receptor family
• pyrin domain-containing
• 3 protein
• receptor for advanced glycation end product

Background-This study aimed at investigating whether NLRP3 (the Nod like receptor family, pyrin domain-containing 3 protein) inflammasome activation induced HMGB1 (high mobility group box-1 protein) secretion and foam cell formation in human vascular smooth muscle cells (VSMCs) and atherosclerosis in ApoE(-/-) mice @@@ Methods and Results-VSMCs or ApoE(-/-) mice were treated with lipopolysaccharides (LPS) and/or ATP or LPS and high-fat diet to induce NLRP3 inflammasome activation. HMGB1 distribution and foam cell formation in VSMCs were characterized. Liver X receptor a and ATP-binding cassette transporter expression were determined. The impact of NLRP3 or receptor for advanced glycation end product silencing, ZYVAD-FMK (caspase-1 inhibitor), glycyrrhizin (HMGB1 inhibitor) or receptor for advanced glycation end product antagonist peptide on HMGB1 secretion, foam cell formation, liver X receptor a and ATP-binding cassette transporter expression was examined. Expression level of HMGB1 in human atherosclerosis obliterans arterial tissues was characterized. Our results found that NLRP3 inflammasome activation promoted foam cell formation and HMGB1 secretion in VSMCs. Extracellular HMGB1 was a key signal molecule in inflammasome activation-mediated foam cell formation. Furthermore, inflammasome activation-induced HMGB1 activity and foam cell formation were achieved by receptor for advanced glycation end product/liver X receptor alpha / ATP-binding cassette transporter glycyrrhizin. Experiments in vivo found glycyrrhizin significantly attenuated the LPS/high-fat diet-induced atherosclerosis and serum HMGB1 levels in mice. Finally, levels of HMGB1 and NLRP3 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 NLRP3 inflammasome activation and plays an important role in VSMCs foam cell formation and atherogenesis by downregulating liver X receptor a and ATP-binding cassette transporter expression through receptor for advanced glycation end product.

• 出版日期2018-10-2
• 单位中山大学