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

被引：20

作者：

An, Junqing ^{[1
]}

Ouyang, Liu ^{[1
]}

Yu, Changjiang ^{[1
]}

Carr, Sean Michael ^{[1
]}

Ramprasath, Tharmarajan ^{[1
]}

Liu, Zhixue ^{[1
]}

Song, Ping ^{[1
]}

Zou, Ming-Hui ^{[1
]}

Ding, Ye ^{[1
]}

机构：

[1] Georgia State Univ, Ctr Mol & Translat Med, 157 Decatur St SE, Atlanta, GA 30303 USA

来源：

THERANOSTICS | 2023年 / 13卷 / 09期

关键词：

Nicotine; lysosomal dysfunction; NLRP3; inflammasome; atherosclerosis; unstable plaque; VSMC; LYSOSOMAL MEMBRANE PERMEABILIZATION; PROTEIN-KINASE ALPHA-2; CIGARETTE-SMOKING; CARDIOVASCULAR-DISEASE; INTRAPLAQUE HEMORRHAGE; RUPTURE; DEATH; PROGRESSION; MODEL; MACROPHAGES;

D O I：

10.7150/thno.81388

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 ofApoe-/- mice. Moreover, nicotine elevated interleukin 1 beta (IL-1 beta) 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-1 beta 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.

引用

页码：2825 / 2842

页数：18

共 75 条

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