High glucose and interleukin-1β downregulate interleukin-1 type I receptor (IL-1RI) in retinal endothelial cells by enhancing its degradation by a lysosome-dependent mechanism

Cytokine ◽  
2010 ◽  
Vol 49 (3) ◽  
pp. 279-286 ◽  
Author(s):  
Célia Aveleira ◽  
Áurea Castilho ◽  
Filipa Baptista ◽  
Núria Simões ◽  
Carolina Fernandes ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
High Glucose ◽  
Interleukin 1 ◽  
Interleukin 1Β ◽  
Type I ◽  
Retinal Endothelial Cells ◽  
Dependent Mechanism

scholarly journals Epac1 Blocks NLRP3 Inflammasome to Reduce IL-1βin Retinal Endothelial Cells and Mouse Retinal Vasculature

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Youde Jiang ◽  
Li Liu ◽  
Elizabeth Curtiss ◽  
Jena J. Steinle
Keyword(s):  
Endothelial Cells ◽  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
High Mobility ◽  
Conditional Knockout ◽  
Retinal Vasculature ◽  
Retinal Endothelial Cells ◽  
Caspase 1

Inflammation is an important component of diabetic retinal damage. We previously reported that a novelβ-adrenergic receptor agonist, Compound 49b, reduced Toll-like receptor 4 (TLR4) signaling in retinal endothelial cells (REC) grown in high glucose. Others reported that TLR4 activates high-mobility group box 1 (HMGB1), which has been associated with the NOD-like receptor 3 (NLRP3) inflammasome. Thus, we hypothesized that Epac1, a downstream mediator ofβ-adrenergic receptors, would block TLR4/HMGB1-mediated stimulation of the NLRP3 inflammasome, leading to reduced cleavage of caspase-1 and interleukin-1 beta (IL-1β). We generated vascular specific conditional knockout mice for Epac1 and used REC grown in normal and high glucose treated with an Epac1 agonist and/or NLRP3 siRNA. Protein analyses were done for Epac1, TLR4, HMGB1, NLRP3, cleaved caspase-1, and IL-1β. Loss of Epac1 in the mouse retinal vasculature significantly increased all of the inflammatory proteins. Epac1 effectively reduced high glucose-induced increases in TLR4, HMGB1, cleaved caspase-1, and IL-1βin REC. Taken together, the data suggest that Epac1 reduces formation of the NLRP3 inflammasome to reduce inflammatory responses in the retinal vasculature.

scholarly journals The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism

PLoS ONE ◽  
2017 ◽  
Vol 12 (8) ◽  
pp. e0180808 ◽  
Author(s):  
Hui He ◽  
Rebecca L. Weir ◽  
Jordan J. Toutounchian ◽  
Jayaprakash Pagadala ◽  
Jena J. Steinle ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Acid Derivative ◽  
Caspase 3 ◽  
Quinic Acid ◽  
Retinal Endothelial Cells ◽  
Dependent Mechanism

scholarly journals Sulodexide reduces glucose induced senescence in human retinal endothelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Gericke ◽  
K. Suminska-Jasińska ◽  
A. Bręborowicz
Keyword(s):  
Endothelial Cells ◽  
High Glucose ◽  
Glucose Concentration ◽  
Chronic Exposure ◽  
Replicative Senescence ◽  
Population Doubling ◽  
Population Doubling Time ◽  
High Glucose Concentration ◽  
Retinal Endothelial Cells

AbstractChronic exposure of retinal endothelium cells to hyperglycemia is the leading cause of diabetic retinopathy. We evaluated the effect of high glucose concentration on senescence in human retinal endothelial cells (HREC) and modulation of that effect by Sulodexide. Experiments were performed on HREC undergoing in vitro replicative senescence in standard medium or medium supplemented with glucose 20 mmol/L (GLU) or mannitol 20 mnol/L (MAN). Effect of Sulodexide 0.5 LRU/mL (SUL) on the process of HREC senescence was studied. Glucose 20 mmol/L accelerates senescence of HREC: population doubling time (+ 58%, p < 0.001) β-galactosidase activity (+ 60%, p < 0.002) intracellular oxidative stress (+ 65%, p < 0.01), expression of p53 gene (+ 118%, p < 0.001). Senescent HREC had also reduced transendothelial electrical resistance (TEER) (− 30%, p < 0.001). Mannitol 20 mmol/L used in the same scenario as glucose did not induce HREC senescence. In HREC exposed to GLU and SUL, the senescent changes were smaller. HREC, which became senescent in the presence of GLU, demonstrated higher expression of genes regulating the synthesis of Il6 and VEGF-A, which was reflected by increased secretion of these cytokines (IL6 + 125%, p < 0.001 vs control and VEGF-A + 124% p < 0.001 vs control). These effects were smaller in the presence of SUL, and additionally, an increase of TEER in the senescent HREC was observed. Chronic exposure of HREC to high glucose concentration in medium accelerates their senescence, and that process is reduced when the cells are simultaneously exposed to Sulodexide. Additionally, Sulodexide decreases the secretion of IL6 and VEGF-A from senescent HREC and increases their TEER.

scholarly journals High Glucose Disrupts Mitochondrial Morphology in Retinal Endothelial Cells

2010 ◽  
Vol 177 (1) ◽  
pp. 447-455 ◽  
Author(s):  
Kyle Trudeau ◽  
Anthony J.A. Molina ◽  
Wen Guo ◽  
Sayon Roy
Keyword(s):  
Endothelial Cells ◽  
High Glucose ◽  
Mitochondrial Morphology ◽  
Retinal Endothelial Cells

Abstract P241: Calpain-1 Is Increased in Mitochondria and Contributes to Mitochondrial ROS Generation in High Glucose--Stimulated Endothelial Cells and Endothelial Dysfunction in Mouse Models of Diabetes

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Qing Zhao ◽  
Futian Tang ◽  
Limei Shan ◽  
Inga Cepinskas ◽  
Gedas Cepinskas ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
High Glucose ◽  
Aortic Ring ◽  
Ros Generation ◽  
Type I ◽  
Ros Production ◽  
Diabetic Mice ◽  
Calpain Activity ◽  
Over Expression ◽  
Mitochondrial Ros

Objectives: Elevated levels of reactive oxygen species (ROS) are the initial source of endothelial dysfunction in diabetes. Calpain has been implicated in diabetic vascular complications. The present study was to investigate the role of calpain in mitochondrial ROS generation in endothelial cells and vascular dysfunction in diabetic mice. Methods: Endothelial cells cultured from human umbilical vein (HUVEC) were stimulated with high glucose. Calpain activity and protein were determined in mitochondria of HUVEC. Intracellular and mitochondrial ROS generation as well as apoptosis were measured. Type I diabetic OVE 26 mice and type II diabetic db/db mice with calpastatin over-expression (OVE26/CAST and db/db-CAST) were generated, respectively. Type I diabetes was also induced in both wild-type and Tg-CAST mice by injection of streptozocin (STZ). The endothelium-dependent relaxation of aortic ring was measured. Results: High glucose significantly increased calpain-1 protein, calpain activity and ROS generation in mitochondria of HUVEC. Pharmacological inhibition of calpain or over-expression of calpastatin abrogated high glucose-induced intracellular ROS production, mitochondrial ROS generation and apoptosis in HUVEC. Incubation of isolated mitochondria with calpain-1 protein significantly induced its ROS generation and the membrane potential. In diabetic mice, calpain activity was induced in aortic vessels, which correlated with an increase in ROS production and protein tyrosine nitration. Over-expression of calpastatin prevented calpain activity, reduced ROS production and inhibited protein tyrosine nitration in diabetic mice. Aortic ring segments from diabetic mice exhibited a significant reduction in vascular relaxation to acetylcholine, which was reversed by over-expression of calpastatin in Tg-CAST, OVE26/CAST and db/db-CAST mice. Conclusions: This study has demonstrated a novel role of calpain in mitochondrial ROS generation, which contributes to apoptosis in endothelial cells during hyperglycemia. Thus, over-expression of calpastatin inhibits reduces ROS production and ameliorates endothelium-dependent vascular dysfunction in mouse models of diabetes.

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