Src Plays an Important Role in AGE-Induced Endothelial Cell Proliferation, Migration, and Tubulogenesis

Li, Peixin; Chen, Deshu; Cui, Yun; Zhang, Weijin; Weng, Jie; Yu, Lei; Chen, Lixian; Chen, Zhen-Feng; Su, Haiying; Yu, Shengxiang; Wu, Jie; Huang, Qiaobing; Guo, Xiaohua

doi:10.3389/fphys.2018.00765

Cited by 32 publications

(27 citation statements)

References 38 publications

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“…Our data are in line with previous studies showing that dicarbonyls induce endothelial dysfunction via oxidative stress, inflammatory responses, senescence or apoptosis (Jang et al, 2017;Liu et al, 2012;Navarrete Santos et al, 2017;Sliman et al, 2010;Wang et al, 2019;Yamawaki and Hara, 2008) and that AGEs interfere via RAGE-dependent signaling processes in endothelial cells (Chen et al, 2020;Li et al, 2018;Ravi et al, 2020). Until now, however, the impact of dicarbonylinduced changes of protein abundance and intracellular protein modifications on endothelial function has not been thoroughly investigated.…”

Section: Discussionsupporting

confidence: 92%

Mapping sites of carboxymethyllysine modification on proteins reveals its consequences for proteostasis and cell proliferation

Sanzo

Spengler

Leheis

et al. 2020

Preprint

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Posttranslational mechanisms play a key role in modifying the abundance and function of cellular proteins. Among these, modification by advanced glycation end products (AGEs) has been shown to accumulate during aging and age-associated diseases but specific protein targets and functional consequences remain largely unexplored. Here, we devised a proteomic strategy to identify specific sites of carboxymethyllysine (CML) modification, one of the most abundant AGEs. We identified over 1000 sites of CML modification in mouse and primary human cells treated with the glycating agent glyoxal. By using quantitative proteomics, we found that protein glycation triggers a proteotoxic response and directly affects the protein degradation machinery. We show that glyoxal induces cell cycle perturbation in primary endothelial cells and that CML modification reduces acetylation of tubulins and impairs microtubule dynamics. Our data demonstrate the relevance of AGE modification for cellular function and pinpoint specific protein networks that might become compromised during aging.

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Section: Discussionsupporting

confidence: 92%

Mapping sites of carboxymethyllysine modification on proteins reveals its consequences for proteostasis and cell proliferation

Sanzo

Spengler

Leheis

et al. 2020

Preprint

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“…Similar phenomena were observed where treatment of cells with Src blockers abolished Src phosphorylation (Figure 6(d)) and VE-Cadherin phosphorylation (Figure 6(e)) induced by IS implying that PP2 has a potential to inhibit the increased activity of Src mediating VE-Cadherin and reduce hyperpermeability induced by IS. These results are also in agreement with studies which reported that phosphorylation of Src gives rise to endothelial hyperpermeability due to stimulation by Advanced Glycation End-products (AGEs) and PP2 downregulated Src expression illustrating that inactivation of Src decreased AGE-induced HUVEC proliferation, migration, and tube formation [62]. Next, we observed the effect of RES on cytosolic AHR and then evaluated coincubation with IS (Figure 7).…”

Section: Discussionsupporting

confidence: 91%

Role of Resveratrol on Indoxyl Sulfate-Induced Endothelial Hyperpermeability via Aryl Hydrocarbon Receptor (AHR)/Src-Dependent Pathway

Assefa

Yan

Gezahegn

et al. 2019

Oxidative Medicine and Cellular Longevity

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Resveratrol (RES), a dietary polyphenol compound, has been shown to possess health benefits due to its anti-inflammatory, antioxidative, and antiatherosclerosis properties. Tryptophan metabolite-derived indoxyl sulfate (IS) is identified as one of the uremic toxins and physiological endogenous ligand/activator of aryl hydrocarbon receptor (AHR), associated with atherosclerosis in chronic kidney disease (CKD) patients. Studies have shown that a high serum level of IS causes deleterious effects on health primarily by inducing oxidative stress and endothelial dysfunction. However, the precise mechanisms are still unclear. Here, we investigated the underlying mechanism of IS effect on endothelial permeability and the role of RES on IS-induced endothelial hyperpermeability via the AHR/Src-dependent pathway. Bovine aorta endothelial cells (BAECs) were cultured and incubated with IS in the presence or absence of RES, and transendothelial electrical resistance (TEER) and permeability of cells were measured. Alongside, AHR, Src kinase, and Vascular Endothelial Cadherin (VE-Cadherin) activation were examined. Our data showed that IS reduced TEER of cells resulting in increased permeability. VE-Cadherin, a vital regulator of endothelial permeability, was also significantly activated in response to IS, which appeared to be associated with changes of endothelial permeability and AHR/Src kinase. Interestingly, in this setting, RES reversed the effect of IS and inhibited the increased activation of Src induced by IS-activated AHR and modulated VE-Cadherin and permeability. CH223191, an inhibitor of AHR, significantly inhibits IS-induced endothelial hyperpermeability. Further analysis with treatment of PP2, an inhibitor of Src abolishing Src activation, suggests downstream factors. All our data indicated that IS upregulated the AHR/Src kinase pathway, and increased endothelial permeability and phosphorylation of VE-Cadherin may be represented and provide new strategies for addressing protective properties of RES against Src kinase involved in AHR-mediated endothelial hyperpermeability. The findings may be crucial for managing diseases in which endothelial permeability is compromised, and the dietary polyphenols are involved.

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“…The MAPKs signaling cascades activated by RAGE can be regulated by the adaptor molecule mDia-1 (diaphanous related formin 1), a member of the GEF (guanine nucleotide exchange factor) family to activate the Rac1/Cdc42 pathway. Moreover, the RAGE cytosolic domain is connected to the tyrosine kinase protein, Src, which is also related to several downstream signal factors, such as ERK1/2, p38 MAPK, JNK (Basta, 2008;Lee et al, 2015;Zhang et al, 2015;Li et al, 2018;Riuzzi et al, 2018). To further explore the signal pathway of the heat-induced hyper-permeability in which RAGE is involved, a series of experiments were conducted, such as transfecting with siRNA, adenovirus, or pre-incubating with blocking antibody.…”

Section: Discussionmentioning

confidence: 99%

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

Zhou

Chen

et al. 2020

Front. Physiol.

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Objective: To 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. Methods: This 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. Results: RAGE 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. Conclusion: This 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.

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Src Plays an Important Role in AGE-Induced Endothelial Cell Proliferation, Migration, and Tubulogenesis

Cited by 32 publications

References 38 publications

Mapping sites of carboxymethyllysine modification on proteins reveals its consequences for proteostasis and cell proliferation

Mapping sites of carboxymethyllysine modification on proteins reveals its consequences for proteostasis and cell proliferation

Role of Resveratrol on Indoxyl Sulfate-Induced Endothelial Hyperpermeability via Aryl Hydrocarbon Receptor (AHR)/Src-Dependent Pathway

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

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