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.

Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway

“…11 Several studies have suggested that ablation of NLRP3 protects endothelial cells from inflammatory damage, leading to attenuation of AS. 12,13 Thus, the NLRP3 inflammasome is proposed to be a key player in the pathogenesis of vascular inflammation. In 2016, Seldin and co-workers 7 showed that TMAO promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-jB (NF-jB).…”

Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction

“…For example bacterial endotoxin LPS, environmental toxins, high fat diet can contribute to endothelial dysfunction by increasing endothelial permeability and subsequently arterial lipid accumulation in the subendothelial space, thereby initiating atherosclerotic plaque development. Other injurious stimuli like thrombin, histamine and other acute inflammatory mediators can act on endothelium to stimulate opening of their intercellular junctions at the level of adherens and tight junctional complexes [57, 58]. It has been well established that loss of the integrity of inter-endothelial tight junctions contributes to enhanced paracellular endothelial permeability and plasma proteins including albumin and visfatin can impair renal tubular or endothelial tight junctions via activation of Nlrp3 inflammasomes [23, 24, 57, 58].…”

“…Other injurious stimuli like thrombin, histamine and other acute inflammatory mediators can act on endothelium to stimulate opening of their intercellular junctions at the level of adherens and tight junctional complexes [57, 58]. It has been well established that loss of the integrity of inter-endothelial tight junctions contributes to enhanced paracellular endothelial permeability and plasma proteins including albumin and visfatin can impair renal tubular or endothelial tight junctions via activation of Nlrp3 inflammasomes [23, 24, 57, 58]. Consistent with these studies, the present study demonstrates that TMAO treatment induces increases in permeability to dextrans in CAECs, via activation of Nlrp3 inflammasomes (Fig.…”

Cathepsin B-Mediated NLRP3 Inflammasome Formation and Activation in Angiotensin II -Induced Hypertensive Mice: Role of Macrophage Digestion Dysfunction

“…As a pattern recognition receptor, NLRP3 is upregulated by stimulation with pathogen-associated molecular patterns (PAMPs) [4], which are recruited by the adapter protein apoptosisassociated speck-like protein containing CARD (ASC), and then converts pro-caspase-1 into cle-caspase-1 (cleaved form) [5]. NLRP3 inflammasome activation transforms proinflammatory cytokines such as interleukin (IL)-1β and IL-18 from their immature "pro" forms to their active forms, which have different effects in different cell types, including phenotypic transformation, cell pyroptosis, and cell membrane permeability [6][7][8]. In macrophages, NLRP3 inflammasome activation is critical in the formation of foam cells and other atherosclerotic lesions in response to proatherogenic stimuli such as cholesterol crystals [9,10].…”