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

Area of Science:

• Cardiovascular Biology
• Cellular Mechanisms of Disease
• Toxicology

Background:

• Cigarette smoking is a significant risk factor for atherosclerosis and cardiovascular diseases.
• Nicotine's detrimental effects on vascular endothelial cells are increasingly recognized, but mechanisms are unclear.
• Cell death and inflammation are key drivers of atherosclerosis development.

Purpose of the Study:

• To investigate the role of pyroptosis in nicotine-induced atherosclerosis.
• To elucidate the cellular and molecular mechanisms linking nicotine exposure to endothelial cell death and inflammation.

Main Methods:

• Atherosclerosis was induced in ApoE-/- mice fed a high-fat diet (HFD) with nicotine exposure.
• Human aortic endothelial cells (HAECs) were treated with nicotine.
• Key markers of pyroptosis, inflammasome activation (NLRP3-ASC-caspase-1), cytokine release (IL-1β, IL-18), and cell death were assessed.
• The role of reactive oxygen species (ROS) was examined using a ROS scavenger (N-acetyl-cysteine, NAC).

Main Results:

• Nicotine exposure led to increased atherosclerotic plaque size and inflammatory cytokine secretion in mice.
• Nicotine induced NLRP3-ASC inflammasome activation and pyroptosis in HAECs, confirmed by caspase-1 cleavage and IL-1β/IL-18 production.
• Inhibition of caspase-1, NLRP3, or ASC suppressed nicotine-induced pyroptosis.
• Reactive oxygen species (ROS) were identified as upstream activators of the nicotine-NLRP3-ASC-pyroptosis pathway.

Conclusions:

• Pyroptosis is a likely cellular mechanism underlying nicotine's pro-atherosclerotic effects.
• Nicotine induces endothelial cell pyroptosis via ROS-mediated activation of the NLRP3 inflammasome.
• Targeting this pathway may offer therapeutic strategies for mitigating smoking-related cardiovascular risks.