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      Contribution of cathepsin B-dependent Nlrp3 inflammasome activation to nicotine-induced endothelial barrier dysfunction

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      European Journal of Pharmacology

      Elsevier BV

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          <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>

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          European Journal of Pharmacology
          European Journal of Pharmacology
          Elsevier BV
          November 2019
          November 2019
          : 172795
          © 2019


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