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Contribution of redox-dependent activation of endothelial Nlrp3 inflammasomes to hyperglycemia-induced endothelial dysfunction
Open accessAbstract
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.Key message 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.
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“Several studies have suggested that ablation of NLRP3 protects endothelial cells from inflammatory damage, leading to attenuation of AS.12, 13”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [13]
In the citing paper
“whereas ablation of NLRP3 protects endothelial cells from inflammatory damage, subsequently attenuating AS.12, 13”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [13]
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“It has also been found that the mtROS‐dependent activation of the endothelial NLRP3 inflammasome by hyperglycemia may be an important initiating mechanism for endothelial dysfunction,13”
From Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway (2017) · cites this paper as [13]
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Metadata
- Authors
- Chen, Y., Wang, L., Pitzer, A. L., Li, X., Li, P.-L., & Zhang, Y.
- Affiliations
- Guangzhou University of Chinese Medicine (CN)
- Virginia Commonwealth University (US)
- University of Houston (US)
- Corresponding author
- Zhang, Yang
- Venue
- Journal of Molecular Medicine
- Published
- 2016-10-25
- Volume
- 94
- Issue
- 12
- Pages
- 1335-1347
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- PMC
- PMC5512566
- OpenAlex
- W2535421876
- Cited by
- 108
- References
- 59
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 9 · 2023: 9 · 2022: 15 · 2021: 12 · 2020: 15 · 2019: 12 · 2018: 11 · 2017: 12 · 2016: 1
- FWCI
- 6.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL122937, HL122769, HL057244)
- National Natural Science Foundation of China (81603587)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Keywords
- NLRP3 inflammasome, endothelial dysfunction, hyperglycemia, diabetes mellitus, tight junction disruption, endothelial hyperpermeability, reactive oxygen species, HMGB1, coronary endothelium, streptozotocin-induced diabetes, vascular endothelial cells, inflammasome activation
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Cell Line, Coronary Vessels, Diabetes Mellitus, Experimental, Endothelium, Vascular, Gene Expression Regulation, Humans, Hyperglycemia, Male, Mice, Inbred C57BL, Oxidation-Reduction, Permeability, Streptozocin, Reactive Oxygen Species, Mice, Knockout, Tight Junctions, HMGB1 Protein, RNA, Small Interfering, Endothelial Cells, Mice, Inflammasomes
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