Research Papers:

Protection by simvastatin on hyperglycemia-induced endothelial dysfunction through inhibiting NLRP3 inflammasomes

Zhen-Huan Lv, Trinh Anh Phuong, Shi-Jie Jin, Xiao-Xue Li and Ming Xu _

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Oncotarget. 2017; 8:91291-91305. https://doi.org/10.18632/oncotarget.20443

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Zhen-Huan Lv1,*, Trinh Anh Phuong1,*, Shi-Jie Jin2, Xiao-Xue Li3 and Ming Xu1

1Department of Clinical Pharmacy, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China

2School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 311400, China

3Department of Pathology, Medical School of Southeast University, Nanjing 210009, China

*These authors have contributed equally to this work

Correspondence to:

Ming Xu, email: [email protected]

Keywords: simvastatin, diabetes, NLRP3 inflammasome, HMGB1, vascular endothelial permeability

Received: April 16, 2017    Accepted: July 25, 2017    Published: August 24, 2017


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.

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