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Role of Src in Vascular Hyperpermeability Induced by Advanced Glycation End Products.

ABSTRACT: The disruption of microvascular barrier in response to advanced glycation end products (AGEs) stimulation contributes to vasculopathy associated with diabetes mellitus. Here, to study the role of Src and its association with moesin, VE-cadherin and focal adhesion kinase (FAK) in AGE-induced vascular hyperpermeability, we verified that AGE induced phosphorylation of Src, causing increased permeability in HUVECs. Cells over-expressed Src displayed a higher permeability after AGE treatment, accompanied with more obvious F-actin rearrangement. Activation of Src with pcDNA3/flag-Src(Y530F) alone duplicated these effects. Inhibition of Src with siRNA, PP2 or pcDNA3/flag-Src(K298M) abolished these effects. The pulmonary microvascular endothelial cells (PMVECs) isolated from receptor for AGEs (RAGE)-knockout mice decreased the phosphorylation of Src and attenuated the barrier dysfunction after AGE-treatment. In vivo study showed that the exudation of dextran from mesenteric venules was increased in AGE-treated mouse. This was attenuated in RAGE knockout or PP2-pretreated mice. Up-regulation of Src activity induced the phosphorylation of moesin, as well as activation and dissociation of VE-cadherin, while down-regulation of Src abolished these effects. FAK was also proved to interact with Src in HUVECs stimulated with AGEs. Our studies demonstrated that Src plays a critical role in AGE-induced microvascular hyperpermeability by phosphorylating moesin, VE-cadherin, and FAK respectively.

SUBMITTER: Zhang W

PROVIDER: S-EPMC4585381 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Role of the Receptor for Advanced Glycation End Products in Heat Stress-Induced Endothelial Hyperpermeability in Acute Lung Injury.

Project description:ObjectiveTo study the role of the receptor for advanced glycation end products (RAGE) in endothelial barrier dysfunction induced by heat stress, to further explore the signal pathway by which RAGE contributes to heat-induced endothelia response, and thereby find a novel target for the clinical treatment of ALI (acute lung injury) induced by heatstroke.MethodsThis study established the animal model of heatstroke using RAGE knockout mice. We observed the role of RAGE in acute lung injury induced by heatstroke in mice by evaluating the leukocytes, neutrophils, and protein concentration in BALF (Bronchoalveolar lavage fluids), lung wet/dry ratio, histopathological changes, and the morphological ultrastructure of lung tissue and arterial blood gas analysis. To further study the mechanism, we established a heat stress model of HUVEC and concentrated on the role of RAGE and its signal pathway in the endothelial barrier dysfunction induced by heat stress, measuring Transendothelial electrical resistance (TEER) and western blot.ResultsRAGE played a key role in acute lung injury induced by heatstroke in mice. The mechanism C-Jun is located in the promoter region of the RAGE gene. C-Jun increased the RAGE protein expression while HSF1 suppressed RAGE protein expression. The overexpressed RAGE protein then increased HUVEC monolayer permeability by activating ERK and P38 MAPK under heat stress.ConclusionThis study indicates the critical role of RAGE in heat stress-induced endothelial hyperpermeability in acute lung injury and suggests that RAGE could be a potential therapeutic target in protecting patients against acute lung injury induced by heatstroke.

| S-EPMC7643755 | biostudies-literature

Advanced glycation end products induce endothelial hyperpermeability via β-catenin phosphorylation and subsequent up-regulation of ADAM10.

Project description:Endothelial hyperpermeability is the initial event in the development of diabetic microvascular complications, and advanced glycation end products (AGEs) are suggested to cause much of the endothelial hyperpermeability associated with diabetes mellitus, but the molecular mechanism remains to be characterized. β-catenin reportedly plays dual functions in maintaining normal endothelial permeability by serving both as an adhesive component and a signal transduction component. Here, we found that AGEs induced the phosphorylation of β-catenin at residues Y654 and Y142 and the endothelial hyperpermeability was reversed when the two residues were blocked. In mechanism, phosphorylation of Y654 was blocked by Src inactivation, whereas phosphorylation of Y142 was reduced by a focal adhesion kinase inhibitor. β-catenin Y654 phosphorylation induced by AGEs facilitated the dissociation of vascular endothelial (VE)-cadherin/β-catenin and the impairment of adherens junctions (AJs), whereas β-catenin Y142 phosphorylation favoured the dissociation of β-catenin and α-catenin. Further investigation revealed that β-catenin Y142 phosphorylation was required for AGEs-mediated β-catenin nuclear translocation, and this nuclear-located β-catenin subsequently activated the TCF/LEF pathway. This pathway promotes the transcription of the Wnt target, ADAM10 (a disintegrin and metalloprotease 10), which mediates VE-cadherin shedding and leads to further impairment of AJs. In summary, our study showed the role of β-catenin Y654 and Y142 phosphorylation in AGEs-mediated endothelial hyperpermeability through VE-cadherin/β-catenin/α-catenin dissociation and up-regulation of ADAM10, thereby advancing our understanding of the underlying mechanisms of AGEs-induced microvascular hyperpermeability.

| S-EPMC8358892 | biostudies-literature

The Interaction between Human Microbes and Advanced Glycation End Products: The Role of <i>Klebsiella</i> X15 on Advanced Glycation End Products' Degradation.

Project description:Previous studies have shown that advanced glycation end products (AGEs) are implicated in the occurrence and progression of numerous diseases, with dietary AGEs being particularly associated with intestinal disorders. In this study, methylglyoxal-beta-lactoglobulin AGEs (MGO-β-LG AGEs) were utilized as the exclusive nitrogen source to investigate the interaction between protein-bound AGEs and human gut microbiota. The high-resolution mass spectrometry analysis of alterations in peptides containing AGEs within metabolites before and after fermentation elucidated the capacity of intestinal microorganisms to enzymatically hydrolyze long-chain AGEs into short-chain counterparts. The 16S rRNA sequencing revealed Klebsiella, Lactobacillus, Escherichia-Shigella, and other genera as dominant microbiota at different fermentation times. A total of 187 potential strains of AGE-metabolizing bacteria were isolated from the fermentation broth at various time points. Notably, one strain of Klebsiella exhibited the most robust growth capacity when AGEs served as the sole nitrogen source. Subsequently, proteomics was employed to compare the changes in protein levels of Klebsiella X15 following cultivation in unmodified proteins and proteins modified with AGEs. This analysis unveiled a remodeled amino acid and energy metabolism pathway in Klebsiella in response to AGEs, indicating that Klebsiella may possess a metabolic pathway specifically tailored to AGEs. This study found that fermenting AGEs in healthy human intestinal microbiota altered the bacterial microbiota structure, especially by increasing Klebsiella proliferation, which could be a key factor in AGEs' role in causing diseases, particularly intestinal inflammation.

| S-EPMC10933965 | biostudies-literature

Transcriptome analysis of Advanced glycation end products treated ligament cells

Project description:Ossification of the posterior longitudinal ligament (OPLL) is formed by heterogeneous ossification of posterior longitudinal ligament. The patho-mechanism of OPLL is still largely unknown. Recently, disorders of metabolism are thought to be the center of many diseases such as OPLL. Advanced glycation end product (AGE) are accumulated in many extracellular matrixes such as ligament fibers, and it can functions as cellular signal through its receptor (RAGE), contributing to various events such as atherosclerosis or oxidative stress. However, its role in OPLL formation is not yet known. Therefore, we performed high-through-put RNA sequencing on primary posterior longitudinal ligament cells treated with different doses of AGEs (1ÂµM, 5ÂµM and negative control), with or without BMP2 (1ÂµM). mRNA profiles of Primary human posterior longitudinal ligament cells stimulated with various stimuli (Control, 1ÂµM AGE-BSA, 5ÂµM AGE-BSA, 1ÂµM AGE-BSA with BMP2, 5ÂµM AGE-BSA with BMP2) were generated by deep sequencing on Ion Proton

2016-02-16 | E-GEOD-65952 | biostudies-arrayexpress

Transcriptome analysis of Advanced glycation end products treated ligament cells

Project description:Ossification of the posterior longitudinal ligament (OPLL) is formed by heterogeneous ossification of posterior longitudinal ligament. The patho-mechanism of OPLL is still largely unknown. Recently, disorders of metabolism are thought to be the center of many diseases such as OPLL. Advanced glycation end product (AGE) are accumulated in many extracellular matrixes such as ligament fibers, and it can functions as cellular signal through its receptor (RAGE), contributing to various events such as atherosclerosis or oxidative stress. However, its role in OPLL formation is not yet known. Therefore, we performed high-through-put RNA sequencing on primary posterior longitudinal ligament cells treated with different doses of AGEs (1µM, 5µM and negative control), with or without BMP2 (1µM).

2016-02-16 | GSE65952 | GEO

Advanced Glycation End Products:Receptors for Advanced Glycation End Products Axis in Coronary Stent Restenosis: A Prospective Study.

Project description:This study was aimed to correlate the pre- and 6-month postpercutaneous coronary intervention (PCI) serum concentrations of advanced glycation end products (AGE), soluble receptors for advanced glycation end products (sRAGE), AGE/sRAGE ratio, and serum malondialdehyde (MDA) levels with in-stent restenosis (ISR) among patients receiving either a drug-eluting stent (DES) or a bare-metal stent (BMS).In-stent restenosis remains as an adverse outcome following PCI. Sixty consecutive nondiabetic, Caucasian male patients, diagnosed with a non-ST-elevation myocardial infarction who received either a DES or BMS via PCI, were enrolled. Baseline levels of serum AGE, sRAGE, AGE/sRAGE ratios, MDA, and angiographic parameters were determined at stenting and at 6 months. Patients with and without ISR at 6 months were compared on both baseline and 6-month biomarker levels and within stent types.The pre-PCI serum AGE levels and AGE/sRAGE ratios were higher in ISR patients compared with non-ISR patients, while the pre-PCI and post-PCI serum sRAGE levels were lower in ISR patients compared with non-ISR patients. The pre and post-PCI levels of MDA were also higher in ISR patients. Comparing stent types, relative levels of MDA between those with and without ISR at the respective time points were similar, although changes between time points appeared type specific.Post-PCI ISR correlates with low serum values of sRAGE and high serum values of AGE, MDA, and AGE/sRAGE ratio which are present at stenting. The associations of baseline AGE, sRAGE, AGE/sRAGE, and MDA levels with ISR appear consistent between stent types.

| S-EPMC6221796 | biostudies-literature

Rosiglitazone protects neuroblastoma cells against advanced glycation end products-induced injury.

Project description:AimTo investigate the protective effects of rosiglitazone (RGZ) against the neuronal toxicity induced by advanced glycation end products (AGEs) and the underlying mechanisms.MethodsNeuroblastoma cell line SH-SY5Y was used. Cell viability and apoptosis were assessed using MTT assay and flow cytometry, respectively. Superoxide dismutase (SOD) and catalase activities were measured using biochemical methods. Intracellular reactive oxygen species (ROS) were monitored using 2',7'-dichlorodihydro-fluorescein diacetate (DCFH-DA). Secreted β-amyloid(1-42) (Aβ(1-42)) level was assessed by ELISA. The expression of mRNA of Bcl2, Bax, Caspase3, Aβ precursor protein (APP), β-site APP-cleaving enzyme 1 (BACE1), and insulin degrading enzyme (IDE) were measured using quantitative real-time PCR (Q-PCR), and their protein levels were examined using Western blot.ResultsRGZ (0.1-10 μmol/L) significantly increased the cell viability that was reduced by AGEs (1000 μg/mL). RGZ (10 μmol/L) significantly ameliorated AGEs-triggered downregulation of SOD and catalase, and production of ROS. It also reversed Bcl2 downregulation, Bax upregulation and Caspase3 expression caused by AGEs. Moreover, it significantly attenuated AGEs-induced Aβ secretion and APP protein upregulation. RGZ did not affect BACE1 expression, but induced IDE expression, which promoted degradation of Aβ. All the effects were blocked by the specific PPARγ antagonist GW9662 (10 μmol/L).ConclusionRGZ protects the euroblastoma cells against AGEs-induced injury via its anti-oxidative, anti-apoptotic and anti-inflammatory properties that seems to be mediated by PPARγ activation. The results suggest a beneficial role for RGZ in the treatment of Alzheimer's disease.

| S-EPMC4002533 | biostudies-literature

Toxicity of advanced glycation end products (Review).

Project description:Advanced glycation end-products (AGEs) are proteins or lipids glycated nonenzymatically by glucose, or other reducing sugars and their derivatives, such as glyceraldehyde, glycolaldehyde, methyloglyoxal and acetaldehyde. There are three different means of AGE formation: i) Maillard reactions, the polyol pathway and lipid peroxidation. AGEs participate in the pathological mechanisms underlying the development of several diseases, such as diabetes and its complications, retinopathy or neuropathy, neurological disorders (for example, Parkinson's disease and Alzheimer's disease), atherosclerosis, hypertension and several types of cancer. AGE levels are increased in patients with hyperglycaemia, and is likely the result of the high concentration of glycation substrates circulating in the blood. The present review summarises the formation and nomenclature of advanced glycation end-products, with an emphasis on the role of AGEs in the development of diabetes, neurological disorders, as well as in cancer and other pathologies. A particular focus is placed on the functions of toxic AGEs. Additionally, studies which have shown the cytotoxicity of glycated albumin and other AGEs are also discussed. Finally, the diagnostic relevance of AGEs as well as for targeting in therapeutic strategies are highlighted.

| S-EPMC7995243 | biostudies-literature

Role of Moesin in Advanced Glycation End Products-Induced Angiogenesis of Human Umbilical Vein Endothelial Cells.

Project description:Disorders of angiogenesis are related to microangiopathies during the development of diabetic vascular complications, but the effect of advanced glycation end products (AGEs) on angiogenesis and the mechanism has not been completely unveiled. We previous demonstrated that moesin belonging to the ezrin-radixin-moesin (ERM) protein family protein played a critical role in AGE-induced hyper-permeability in human umbilical vein endothelial cells (HUVECs). Here, we investigated the impact of moesin on AGE-induced HUVEC proliferation, migration, and tubulogenesis. Silencing of moesin decreased cell motility and tube formation but not cell proliferation. It also attenuated cellular F-actin reassembly. Further, phosphorylation of threonine at the 558 amino acid residue (Thr 558) in moesin suppressed AGE-induced HUVEC proliferation, migration, and tube formation, while the activating mutation of moesin at Thr 558 enhanced HUVEC angiogenesis. Further, the inhibition of either RhoA activity by adenovirus or ROCK activation with inhibitor Y27632 decreased AGE-induced moesin phosphorylation and subsequently suppressed HUVEC angiogenesis. These results indicate that the Thr 558 phosphorylation in moesin mediates endothelial angiogenesis. AGEs promoted HUVEC angiogenesis by inducing moesin phosphorylation via RhoA/ROCK pathway.

| S-EPMC4783699 | biostudies-literature

Peroxidasin promotes diabetic vascular endothelial dysfunction induced by advanced glycation end products via NOX2/HOCl/Akt/eNOS pathway.

Project description:Reactive oxygen species (ROS) derived from NADPH oxidases (NOX) plays an essential role in advanced glycation end products (AGEs)-induced diabetic vascular endothelial dysfunction. Peroxidasin (PXDN, VPO1) is one member of peroxidases family that catalyzes hydrogen peroxide (H2O2) to hypochlorous acid (HOCl). This present study aimed to elucidate the role of PXDN in promoting vascular endothelial dysfunction induced by AGEs in diabetes mellitus. We found that, compared to non-diabetic (db/m) mice, PXDN expression was notably increased in db/db mice with impaired endothelium-dependent relaxation. Knockdown of PXDN in vivo through tail vein injection of siRNA restored the impaired endothelium-dependent relaxation function of db/db mice which is accompanied with up-regulation of eNOS Ser1177 phosphorylation and NO production. AGEs significantly elevated expression of PXDN and 3-Cl-Tyr, but decreased phosphorylation of Akt and eNOS and NO release in HUVECs. All these effects induced by AGEs were remarkable alleviated by silencing PXDN with small interfering RNAs. In addition, HOCl treatment alone as well as HOCl added with Akt inhibitor MK2206 inhibited phosphorylation of Akt and eNOS, reducing NO production. More importantly,AGEs-induced up-regulation of PXDN and 3-Cl-Tyr with endothelial dysfunction were transformed by NOX2 silencing and H2O2 scavengers. Thus, these results support the conclusion that PXDN promotes AGEs-induced diabetic vascular endothelial dysfunction by attenuating eNOS phosphorylation at Ser1177 via NOX2/HOCl/Akt pathway.

| S-EPMC8192873 | biostudies-literature

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