Aspirin alleviates endothelial gap junction dysfunction through inhibition of NLRP3 inflammasome activation in LPS-induced vascular injury

Abstract

The loss of endothelial connective integrity and endothelial barrier dysfunction can lead to increased vascular injury, which is related to the activation of endothelial inflammasomes. There are evidences that low concentrations of aspirin can effectively prevent cardiovascular diseases. We hypothesized that low-dose aspirin could ameliorate endothelial injury by inhibiting the activation of NLRP3 inflammasomes and ultimately prevent cardiovascular diseases. Microvascular endothelial cells were stimulated by lipopolysaccharide (2 μg/mL) and administrated by 0.1–2 mmol/L aspirin. The wild type mice were stimulated with LPS (100 μg/kg/day), and 1 h later treated with aspirin (12.5, 62.5, or 125 mg/kg/day) and dexamethasone (0.0182 mg/kg/day) for 7 days. Plasma and heart were harvested for measurement of ELISA and immunofluorescence analyses. We found that aspirin could inhibit NLRP3 inflammasome formation and activation in vitro in dose-dependent manner and has correlation between the NLRP3 inflammasome and the ROS/TXNIP pathway. We also found that low-concentration aspirin could inhibit the formation and activation of NLRP3 inflammasome and restore the expression of the endothelial tight junction protein zonula occludens-1/2 (ZO1/2). We assume that aspirin can ameliorate the endothelial layer dysfunction by suppressing the activation of NLRP3 inflammasome.

Contribution of TGF-Beta-Mediated NLRP3-HMGB1 Activation to Tubulointerstitial Fibrosis in Rat With Angiotensin II-Induced Chronic Kidney Disease

“…Our data show that Ang II infusion induced the activation of NLRP3 inflammasomes in rat kidneys (Figures 2A-D). Previous studies have revealed the role of NLRP3 inflammasomes in mediating the release of HMGB1 (Lamkanfi et al, 2010;Chen et al, 2015;Zhou et al, 2019). Several reports have identified that HMGB1, a member of the high mobility group nuclear protein family, acts as a nuclear homeostasis DNA-binding protein (Paudel et al, 2019).…”

NLRP3 inflammasome in endothelial dysfunction

“…Aspirin is one of the most commonly used drugs for the secondary prevention of cardiovascular disease 104 . Zhou et al found that aspirin protects the expression of ZO-1 and ZO-2 by inhibiting NLRP3 inflammasome formation and activation in LPS-induced MVECs and coronary arterial endothelium, thereby alleviating endothelial gap junction dysfunction 105 . This study unraveled a novel mechanism of aspirin in ameliorating endothelial dysfunction by blocking redox signaling and NLRP3 inflammasome activation, providing a new viewpoint on the clinical potential of aspirin in the early prevention of cardiovascular diseases 105 .…”

“…Zhou et al found that aspirin protects the expression of ZO-1 and ZO-2 by inhibiting NLRP3 inflammasome formation and activation in LPS-induced MVECs and coronary arterial endothelium, thereby alleviating endothelial gap junction dysfunction 105 . This study unraveled a novel mechanism of aspirin in ameliorating endothelial dysfunction by blocking redox signaling and NLRP3 inflammasome activation, providing a new viewpoint on the clinical potential of aspirin in the early prevention of cardiovascular diseases 105 . The mitochondrion-targeting antioxidant mitoquinone (MitoQ) was found to inhibit endothelial inflammation and barrier injury in cigarette smoke extract (CSE)-treated HUVECs via restoring mitochondrial damage 106 .…”

Oroxindin inhibits macrophage NLRP3 inflammasome activation in DSS-induced ulcerative colitis in mice via suppressing TXNIP-dependent NF-κB pathway

“…For immunofluorescence, the sections were incubated with anti-F4/80 (1:100) plus anti-NLRP3 (1:100) or anti-caspase-1 (1:100) antibodies overnight. On the next day, the slides were washed and labeled with corresponding conjugated secondary antibodies (Alexa Fluor 488 and Dylight 594) for 2 h. Then, slides were visualized sequentially using a laser scanning confocal microscope (ZEN2.3, Zeiss) [ 30 , 31 ]. Settings for image acquisition were identical for both control and experimental tissues.…”