Abstract
Recent studies have demonstrated that NLRP3 inflammasome complex acts as pivotal elements to initiate inflammatory responses and plays an important role in the dysfunction of cardiovascular complications. Meanwhile, simvastatin prevents vascular endothelial dysfunction from inflammasome invasion contributing to reduce cardiovascular risk. However, Whether or not the simvastatin improves vascular endothelial barrier function through inhibiting the activation of NLRP3 inflammasome pathway remains unknown. Here, we explored the role and mechanisms of simvastatin in the activation of NLRP3 inflammasome which are involved in vascular endothelial hyperpermeability causing by the disruption of tight junction protein ZO-1 and adherens junction protein VE-Cadherin, an early initiation of cardiovascular complication. Our results found that high glucose significantly induced the formation and activation of NLRP3 inflammasome through NADPH oxidase-dependent reactive oxygen species (ROS) formation, associated with vascular endothelial hyperpermeability causing by ZO-1 and VE-Cadherin disruption in the rat aortic endothelial cells (RAECs). Simvastatin treatment remarkably abolished vascular endothelial hyperpermeability and enhanced the protein expression of ZO-1 and VE-Cadherin through NLRP3 inflammasome. Mechanistically, the inhibitory role of simvastatin endothelial hyperpermeability is attributed to the decreased release of cytoplasmic high mobility group box protein-1 (HMGB1) derived from endothelial NLRP3 inflammasome activation. We further confirm the protective role of simvastatin on vascular leakage in the heart of diabetic rats injected with Evans blue dye, which was associated with HMGB1 release in the serum. Collectively, the mechanism of simvastatin treatment alleviating vascular endothelial permeability dysfunction may be through inhibiting the NLRP3 inflammasome-dependent HMGB1 release in RAECs.
Highlights
Studies have demonstrated a central role of inflammasome in the pathogenesis of cardiovascular diseases including atherosclerosis [1], hypertension [2], vascular inflammation [3] and cardiac remodeling [4]
We further found that glucose dose-dependently enhanced caspase-1 activity in rat aortic endothelial cells (RAECs) exposed under 20, 30, and 40 mmol/l glucose (Figure 1C), which is consist with the increase of IL-1β release, a primary caspase-1 substrate, in cell supernatants as measured by commercially available ELISA kit (Figure 1D)
RAECs were treated with different doses simvastatin, and it is found that 5μM simvastatin had the most significant effects on NLRP3 protein expression with no significant effects on cell viability with MTT assay (Supplementary Figure 1)
Summary
Studies have demonstrated a central role of inflammasome in the pathogenesis of cardiovascular diseases including atherosclerosis [1], hypertension [2], vascular inflammation [3] and cardiac remodeling [4]. On the other hand, accumulating evidence indicate that inflammasome activation can cause cell dysfunction or injury via non-canonical actions through pyroptosis, interference with cytoskeleton arrangement, lipid handling, or direct regulation of synthesis, www.impactjournals.com/oncotarget metabolism, or secretion of functional proteins [7, 8]. In this respective, we recently reported that such non-canonical role of inflammasome was involved in endothelial dysfunction and injury during obesity [9, 10]. The present study hypothesized that inhibited NLRP3 inflammasome by simvastatin is an important mechanism leading to their preventive effects on vascular endothelial cells
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