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Advanced glycosylation end products (AGEs) controls proliferation, invasion and permeability through orchestrating ARHGAP18/RhoA pathway in human umbilical vein endothelial cells

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Abstract

Diabetic vascular complications caused by endothelial dysfunction play an important role in the pathogenesis of diabetic foot. A well understanding of the role of endothelial dysfunction in diabetic foot vasculopathy will help to further reveal the pathogenesis of diabetic foot. This study aimed to assess whether the RhoA/ROCK signaling pathway is controlled by Rho GTPase-activating proteins (RhoGAP, ARHGAP) and advanced glycosylation end products (AGEs), and to clarify the roles of ARHGAP and AGEs in the RhoA/ROCK signaling pathway or the mechanism by which AGEs regulated RhoA. Real-time PCR was applied to detect gene expression. Manipulation of endothelial biological functions by ARHGAP18 and AGEs were studied via cell counting kit-8 (CCK-8), Western blot, transwell, FITC-Dextran and TEER permeability experiments. RhoA-specific inhibitor Y-27632 was used to silence the activity of RhoA. Dual Luciferase Reporter Assay, Western blot and ELISA assays were used to detect molecular mechanism of endothelial biological functions. In this study, we found that ARHGAP18 was negatively correlated with RhoA, and the expression of ARHGAP18 in human umbilical vein endothelial cells (HUVECs) was decreased with gradient-increased AGEs. Furthermore, AGEs and ARHGAP18 could orchestrate RhoA activity, then activate NF-κB signaling pathway, affect the structural and morphological of VE-cadherin and tight junction protein, and cause endothelial cell contraction, thereby increasing permeability of endothelial cells. In conclusion, AGEs and ARHGAP18 orchestrate cell proliferation, invasion and permeability by controlling the RhoA/ROCK signaling pathway, affecting NF-κB signaling pathway as well as the structure and morphology of VE-cadherin and tight junction protein, and regulating endothelial cell contraction.

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Acknowledgments

We sincerely acknowledged the assistance given by the Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, P.R. China.

Funding

This study was funded by Health Bureau of Qingpu District of Shanghai (No.W2018–18).

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Authors and Affiliations

  1. Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 9/F, Building 7, East Park Road No.1158, Qingpu District, Shanghai, 201700, People’s Republic of China

    Xu Li, Yue Tao, Xiaojun Wang, Tao Wang & Jianjun Liu

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  1. Xu Li
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  2. Yue Tao
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  3. Xiaojun Wang
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  4. Tao Wang
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  5. Jianjun Liu
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Correspondence to Jianjun Liu.

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The authors declare that they have no financial or non-financial competing interests.

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This research involved human participants. All procedures performed in studies involving animals were in accordance with the ethical standards of Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, P.R. China and with the 1964 Declaration of Helsinki and its later amendments.

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Informed consent was obtained from all participants prior to their enrollment in the study.

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Xu Li and Yue Tao are Co-first author

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Li, X., Tao, Y., Wang, X. et al. Advanced glycosylation end products (AGEs) controls proliferation, invasion and permeability through orchestrating ARHGAP18/RhoA pathway in human umbilical vein endothelial cells. Glycoconj J 37, 209–219 (2020). https://doi.org/10.1007/s10719-020-09908-0

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  • DOI: https://doi.org/10.1007/s10719-020-09908-0

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