title: Contribution of redox-dependent activation of endothelial Nlrp3 inflammasomes to hyperglycemia-induced endothelial dysfunction.
abstract: Recent studies indicate that inflammasomes serve as intracellular machinery to initiate classical cytokine-mediated inflammatory responses and play a crucial role in the pathogenesis of cardiovascular diseases. However, whether or not the activation of endothelial inflammasomes directly causes cell dysfunction or tissue injury without recruitment of inflammatory cells is unknown. We explored the role of endothelial cell inflammasome activation in mediating tight junction disruption, a hallmark event of endothelial barrier dysfunction leading to endothelial hyperpermeability in diabetes. We used confocal microscopy to study the formation and activation of NOD-like receptor family pyrin domain containing-3 (Nlrp3) inflammasomes and expression of tight junction proteins in coronary arteries of streptozotocin-treated diabetic wild type and Nlrp3 gene-deleted mice. We found that Nlrp3 ablation prevented inflammasome activation and tight junction disassembly in the coronary arterial endothelium of diabetic mice. Similarly, Nlrp3 gene silencing prevented high glucose-induced down-regulation of tight junction proteins in cultured mouse vascular endothelial cells (MVECs). The high glucose-induced tight junction disruption and consequent endothelial permeability were attributed to increased release of the high mobility group box protein-1 (HMGB1), which is dependent on enhanced Nlrp3 inflammasome activity. Mechanistically, reducing reactive oxygen species (ROS) production abolished high glucose-induced inflammasome activation, tight junction disruption, and endothelial hyperpermeability in MVECs. Collectively, the ROS-dependent activation of endothelial Nlrp3 inflammasomes by hyperglycemia may be an important initiating mechanism to cause endothelial dysfunction. These effects could contribute to the early onset of endothelial injury in diabetes.
  
  
  
  Endothelial tight junction disruption in diabetes requires Nlrp3 inflammasomes. High glucose activates Nlrp3 inflammasome in endothelial cells via ROS production. Activation of endothelial inflammasome by high glucose triggers release of HMGB1. Blockade of Nlrp3/HMGB1 axis inhibits high glucose-induced endothelial permeability.
authors: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, 51006, China.|Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors: Yang
authors: Y
authors: Chen
authors: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors: Lei
authors: L
authors: Wang
authors: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors: Ashley L
authors: AL
authors: Pitzer
authors: Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204-5056, USA.
authors: Xiang
authors: X
authors: Li
authors: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.
authors: Pin-Lan
authors: PL
authors: Li
authors: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA. yzhan219@central.uh.edu.|Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204-5056, USA. yzhan219@central.uh.edu.
authors: Yang
authors: http://orcid.org/0000-0002-8338-3013
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D010084:Oxidation-Reduction; D010539:Permeability; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013311:Streptozocin
keywords: Diabetes; Endothelium; High glucose; Nlrp3 inflammasome; Tight junction proteins