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Jing Jin 1 Article
Basic Research
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Hyperglycemia-Suppressed SMARCA5 Disrupts Transcriptional Homeostasis to Facilitate Endothelial Dysfunction in Diabetes
Ju Wang, Hui Zhou, Jinhua Shao, Shu Zhang, Jing Jin
Diabetes Metab J. 2023;47(3):366-381.   Published online March 6, 2023
DOI: https://doi.org/10.4093/dmj.2022.0179
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Dysfunction of vascular endothelial cells (ECs) plays a central role in the pathogenesis of cardiovascular complications in diabetes. SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5) is a key regulator of chromatin structure and DNA repair, but its role in ECs remains surprisingly unexplored. The current study was designed to elucidate the regulated expression and function of SMARCA5 in diabetic ECs.
Methods
SMARCA5 expression was evaluated in ECs from diabetic mouse and human circulating CD34+ cells using quantitative reverse transcription polymerase chain reaction and Western blot. Effects of SMARCA5 manipulation on ECs function were evaluated using cell migration, in vitro tube formation and in vivo wound healing assays. Interaction among oxidative stress, SMARCA5 and transcriptional reprogramming was elucidated using luciferase reporter assay, electrophoretic mobility shift assay and chromatin immunoprecipitation.
Results
Endothelial SMARCA5 expression was significantly decreased in diabetic rodents and humans. Hyperglycemia-suppressed SMARCA5 impaired EC migration and tube formation in vitro, and blunted vasculogenesis in vivo. Contrarily, overexpression of SMARCA5 in situ by a SMARCA5 adenovirus-incorporated hydrogel effectively promoted the rate of wound healing in a dorsal skin punch injury model of diabetic mice. Mechanistically, hyperglycemia-elicited oxidative stress suppressed SMARCA5 transactivation in a signal transducer and activator of transcription 3 (STAT3)-dependent manner. Moreover, SMARCA5 maintained transcriptional homeostasis of several pro-angiogenic factors through both direct and indirect chromatin-remodeling mechanisms. In contrast, depletion of SMARCA5 disrupted transcriptional homeostasis to render ECs unresponsive to established angiogenic factors, which ultimately resulted in endothelial dysfunction in diabetes.
Conclusion
Suppression of endothelial SMARCA5 contributes to, at least in part, multiple aspects of endothelial dysfunction, which may thereby exacerbate cardiovascular complications in diabetes.

Citations

Citations to this article as recorded by  
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    Xiaoqian Yang, Yuelong Wang, Jingfeng Li, Yuxing Tai, Kunping Yang, Jingwei Lv, Jiaming Sun, Hui Zhang
    Frontiers in Chemistry.2024;[Epub]     CrossRef
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    Kailing Wang, Fan Liu, Budumu Muchu, Jiawen Deng, Jing Peng, Yan Xu, Fujun Li, Miao Ouyang
    Archives of Pharmacal Research.2024; 47(7): 645.     CrossRef
  • USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer
    Sheng Li, Situ Xiong, Zhongqi Li, Lin Yang, Hailang Yang, Jing Xiong, Wang Pan, Ju Guo, Songhui Xu, Bin Fu
    Cell Death & Disease.2024;[Epub]     CrossRef
  • Overexpression of Chromatin Remodeling Factor SRG3 Down-Regulates IL1β-Expressing M1 Macrophages and IL17-Producing T Cells in Adipose Tissues
    Jungmin Jeon, Sung Won Lee, Hyun Jung Park, Yun Hoo Park, Tae-Cheol Kim, Sujin Lee, Seyeong Lee, Luc Van Kaer, Seokmann Hong
    International Journal of Molecular Sciences.2024; 25(21): 11681.     CrossRef

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