Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis

• Published in: Cell death & disease 2018-02, Vol.9 (2), p.171-12, Article 171
• Main Authors: Wu, Xianxian, Zhang, Haiying, Qi, Wei, Zhang, Ying, Li, Jiamin, Li, Zhange, Lin, Yuan, Bai, Xue, Liu, Xin, Chen, Xiaohui, Yang, Huan, Xu, Chaoqian, Zhang, Yong, Yang, Baofeng
• Format: Article
• Language: English
• Subjects: 13/89; 14/19; 14/63; 64/60; 82/29; Acetylcysteine; Animals; Antibodies; Aorta; Aorta - drug effects; Aorta - pathology; Apolipoprotein E; Apolipoproteins E - deficiency; Apolipoproteins E - metabolism; Arteriosclerosis; Atherosclerosis; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biochemistry; Biomedical and Life Sciences; CARD Signaling Adaptor Proteins - metabolism; Cardiovascular diseases; Cardiovascular system; Caspase; Caspase 1 - metabolism; Caspase Inhibitors - pharmacology; Caspase-1; Cell Biology; Cell Culture; Cell death; Cigarette smoking; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; High fat diet; Humans; Immunology; Inflammasomes; Inflammasomes - metabolism; Inflammation; Interleukin 18; Interleukin-18 - metabolism; Interleukin-1beta - metabolism; Life Sciences; Mice; Models, Biological; Nicotine; Nicotine - toxicity; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Plaques; Propidium iodide; Pyroptosis; Pyroptosis - drug effects; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; siRNA
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-017-0257-3

Cigarette smoking is a major risk factor for atherosclerosis and other cardiovascular diseases. Increasing evidence has demonstrated that nicotine impairs the cardiovascular system by targeting vascular endothelial cells, but the underlying mechanisms remain obscure. It is known that cell death and inflammation are crucial processes leading to atherosclerosis. We proposed that pyroptosis may be implicated in nicotine-induced atherosclerosis and therefore conducted the present study. We found that nicotine resulted in larger atherosclerotic plaques and secretion of inflammatory cytokines in ApoE −/− mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with nicotine resulted in NLRP3-ASC inflammasome activation and pyroptosis, as evidenced by cleavage of caspase-1, production of downstream interleukin (IL)-1β and IL-18, and elevation of LDH activity and increase of propidium iodide (PI) positive cells, which were all inhibited by caspase-1 inhibitor. Moreover, silencing NLRP3 or ASC by small interfering RNA efficiently suppressed nicotine-induced caspase-1 cleavage, IL-18 and IL-1β production, and pyroptosis in HAECs. Further experiments revealed that the nicotine-NLRP3-ASC-pyroptosis pathway was activated by reactive oxygen species (ROS), since ROS scavenger (N-acetyl-cysteine, NAC) prevented endothelial cell pyroptosis. We conclude that pyroptosis is likely a cellular mechanism for the pro-atherosclerotic property of nicotine and stimulation of ROS to activate NLRP3 inflammasome is a signaling mechanism for nicotine-induced pyroptosis.