Aspirin alleviates endothelial gap junction dysfunction through inhibition of NLRP3 inflammasome activation in LPS-induced vascular injury
Xing Zhou,a Yanjiao Wu,a Lifeng Ye,a Yunting Wang,a Kaimin Zhang,a Lingjun Wang,d Yi Huang,b Lei Wang,a Shaoxiang Xian,d Yang Zhang,c,⁎⁎ and Yang Chena,⁎.
Aspirin inhibits the ROS–TXNIP signaling pathway to suppress NLRP3 inflammasome, thereby inhibits the activation of HMGB1–RAGE axis and eventually restores the tight junction proteins and permeability.
Inflammasomes are important signaling platform of the innate immune system, poised to detect a wide range of molecular signatures including pathogens and sterile agents. They are multiprotein complexes response of the innate immune system to a noxious stimulus, including infections or tissue damage. Recent studies have found the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome play an important role in the development of cardiovascular diseases9., 10.. Several molecular signaling pathways are shown to mediate the activation of the NLRP3 inflammasome, such as releasing of reactive oxygen species (ROS), lysosome leakage and activation of cathepsin B or the modifications in K+ efflux11., 12., 13., 14., 15., 16.. Then the activation of NLRP3 inflammasome triggers a series of downstream inflammatory factors, leading to vascular endothelial dysfunction and the ultimate occurrence or development of cardiovascular diseases.
In this study, we demonstrated a novel role of aspirin in LPS-induced inter-endothelial junction disruption for the first time. Our findings showed that aspirin protected the expression of inter-endothelial junction proteins including zonula occludens-1 (ZO-1) and zonula occludens-2 (ZO-2) by inhibiting NLRP3 inflammasome pathway. The binding of LPS with TLR4 increases ROS release and NLRP3 inflammasome activation, leading to pyroptosis and tissue damages17., 18.. NLRP3 inflammasome activation is mediated by thioredoxin-interacting protein (TXNIP)19. And recent work demonstrated that NLRP3 inflammasome induced the release of high mobility group box 1 (HMGB1) to cause endothelial dysfunction20., 21.. In addition, aspirin was proved to play a key role in interdicting redox signaling and inhibiting NLRP3 inflammasome, thereby reduce endothelial injury and vascular endothelial dysfunction. Our study implicates the clinical potential of aspirin for the prevention of chronic vasculopathy on the early stage.
