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Abstract
<p class="first" id="P1">Recent studies indicate that endothelial Nlrp3 inflammasome
is critically involved
in the development of cardiovascular complications. However, it remains unknown whether
endothelial inflammasome is involved in endothelial barrier dysfunction associated
with smoking. This study aims to investigate the role of endothelial Nlrp3 inflammasome
in nicotine-induced disruption of inter-endothelial tight junctions and consequent
endothelial barrier dysfunction. The confocal microscopic analysis demonstrated that
mice treated with nicotine exhibited disrupted inter-endothelial tight junctions as
shown by decreased ZO-1 and ZO-2 expression in the coronary arterial endothelium,
whereas the decreases in ZO-1/2 were prevented by Nlrp3 gene deficiency. In cultured
endothelial cells, nicotine caused Nlrp3 inflammasome complex formation and enhances
the inflammasome activity as shown by increased cleavage of pro-caspase-1, and interleukin-1β
(IL-1β) production. Further, nicotine disrupted tight junction and increased permeability
in an endothelial cell monolayer, and this nicotine-induced effect was prevented by
silencing of Nlrp3 gene, inhibition of caspase-1, or blockade of high mobility group
box 1 (HMGB1). Nicotine increased endothelial cell lysosomal membrane permeability
and triggered the lysosomal release of cathepsin B, whereas these events were prevented
by pretreating cells with a lysosome stabilizing agent, dexamethasone. Collectively,
our data suggest that nicotine enhances cathepsin B-dependent Nlrp3 inflammasome activation
and the consequent production of a novel permeability factor HMGB1, which causes disruption
of inter-endothelial tight junctions leading to endothelial hyperpermeability. Instigation
of endothelial inflammasomes may serve as an important pathogenic mechanism contributing
to the early onset of vasculopathy associated with smoking.
</p>