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Theranostics 2023; 13(9):2825-2842. doi:10.7150/thno.81388 This issue Cite

Research Paper

Nicotine exacerbates atherosclerosis and plaque instability via NLRP3 inflammasome activation in vascular smooth muscle cells

Junqing An#, Liu Ouyang#, Changjiang Yu, Sean Michael Carr, Tharmarajan Ramprasath, Zhixue Liu, Ping Song, Ming-Hui Zou, Ye Ding✉

Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA 30303, USA.
# All authors contributed equally to this work.

✉ Corresponding author: Ye Ding, Ph.D., Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA, 30303, USA. Phone: 404-413-6630; E-mail: yding5edu.

Citation:
An J, Ouyang L, Yu C, Carr SM, Ramprasath T, Liu Z, Song P, Zou MH, Ding Y. Nicotine exacerbates atherosclerosis and plaque instability via NLRP3 inflammasome activation in vascular smooth muscle cells. Theranostics 2023; 13(9):2825-2842. doi:10.7150/thno.81388. https://www.thno.org/v13p2825.htm
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Abstract

Graphic abstract

Rationale: Nicotine has been reported to be a strong risk factor for atherosclerosis. However, the underlying mechanism by which nicotine controls atherosclerotic plaque stability remain largely unknown.

Objective: The aim of this study was to evaluate the impact of lysosomal dysfunction mediated NLRP3 inflammasome activation in vascular smooth muscle cell (VSMC) on atherosclerotic plaque formation and stability in advanced atherosclerosis at the brachiocephalic arteries (BA).

Methods and Results: Features of atherosclerotic plaque stability and the markers for NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome were monitored in the BA from nicotine or vehicle-treated apolipoprotein E deficient (Apoe-/-) mice fed with Western-type diet (WD). Nicotine treatment for 6 weeks accelerated atherosclerotic plaque formation and enhanced the hallmarks of plaque instability in BA of Apoe-/- mice. Moreover, nicotine elevated interleukin 1 beta (IL-1β) in serum and aorta and was preferred to activate NLRP3 inflammasome in aortic vascular smooth muscle cells (VSMC). Importantly, pharmacological inhibition of Caspase1, a key downstream target of NLRP3 inflammasome complex, and genetic inactivation of NLRP3 significantly restrained nicotine-elevated IL-1β in serum and aorta, as well as nicotine-stimulated atherosclerotic plaque formation and plaque destabilization in BA. We further confirmed the role of VSMC-derived NLRP3 inflammasome in nicotine-induced plaque instability by using VSMC specific TXNIP (upstream regulator of NLRP3 inflammasome) deletion mice. Mechanistic study further showed that nicotine induced lysosomal dysfunction resulted in cathepsin B cytoplasmic release. Inhibition or knockdown of cathepsin B blocked nicotine-dependent inflammasome activation.

Conclusions: Nicotine promotes atherosclerotic plaque instability by lysosomal dysfunction-mediated NLRP3 inflammasome activation in vascular smooth muscle cells.

Keywords: Nicotine, lysosomal dysfunction, NLRP3 inflammasome, atherosclerosis, unstable plaque, VSMC

Citation styles

APA
An, J., Ouyang, L., Yu, C., Carr, S.M., Ramprasath, T., Liu, Z., Song, P., Zou, M.H., Ding, Y. (2023). Nicotine exacerbates atherosclerosis and plaque instability via NLRP3 inflammasome activation in vascular smooth muscle cells. Theranostics, 13(9), 2825-2842. https://doi.org/10.7150/thno.81388.

ACS
An, J.; Ouyang, L.; Yu, C.; Carr, S.M.; Ramprasath, T.; Liu, Z.; Song, P.; Zou, M.H.; Ding, Y. Nicotine exacerbates atherosclerosis and plaque instability via NLRP3 inflammasome activation in vascular smooth muscle cells. Theranostics 2023, 13 (9), 2825-2842. DOI: 10.7150/thno.81388.

NLM
An J, Ouyang L, Yu C, Carr SM, Ramprasath T, Liu Z, Song P, Zou MH, Ding Y. Nicotine exacerbates atherosclerosis and plaque instability via NLRP3 inflammasome activation in vascular smooth muscle cells. Theranostics 2023; 13(9):2825-2842. doi:10.7150/thno.81388. https://www.thno.org/v13p2825.htm

CSE
An J, Ouyang L, Yu C, Carr SM, Ramprasath T, Liu Z, Song P, Zou MH, Ding Y. 2023. Nicotine exacerbates atherosclerosis and plaque instability via NLRP3 inflammasome activation in vascular smooth muscle cells. Theranostics. 13(9):2825-2842.

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