Research Paper Volume 13, Issue 5 pp 7627—7643
Nicotine exacerbates atherosclerosis through a macrophage-mediated endothelial injury pathway
- 1 Department of Cardiology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China
Received: October 21, 2020 Accepted: January 14, 2021 Published: February 24, 2021https://doi.org/10.18632/aging.202660
How to Cite
Copyright: © 2021 Mao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Evidence suggests that nicotine intake promotes atherosclerosis. We enrolled 100 patients with coronary heart disease (CHD) and found that plaque burden, TXNIP expression, and inflammatory chemokine levels were higher in smokers than non-smokers. Additionally, patients with higher TXNIP expression in peripheral blood mononuclear cells (PBMCs) had a higher Gensini Scores and higher plasma IL-1β and IL-18 levels. Treating bone marrow-derived macrophages (BMDMs) with nicotine in vitro led to enhanced lipid phagocytosis, chemotaxis, and increased production of reactive oxygen species (ROS), which activated TXNIP/NLRP3 inflammasome signaling and promoted pyroptosis, as evidenced by caspase-1 cleavage and increased production of IL-1β, IL-18, and gasdermin D. Nicotine intake by ApoE(-/-) mice fed a high-fat diet recapitulated those phenotypes. The effects of nicotine on pyroptotic signaling were reversed by N-acetyl-cysteine, a ROS scavenger. Silencing TXNIP in vivo reversed the effects of nicotine on macrophage invasion and vascular injury. Nicotine also induced pyroptotic macrophages that contributed to the apoptotic death of endothelial cells. These findings suggest that nicotine accelerates atherosclerosis in part by promoting macrophage pyroptosis and endothelial damage. Therefore, targeting the TXNIP/NLRP3-mediated pyroptotic pathway in macrophages may ameliorate nicotine-induced endothelial damage.