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M1 linear ubiquitination of LKB1 inhibits vascular endothelial cell injury in atherosclerosis through activation of AMPK

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Abstract

Endothelial cell injury is confirmed to be the initial step in the atherosclerosis (AS) process. Here, we tried to elucidate the role of liver kinase B1 (LKB1) and adenosine phosphate protein kinase (AMPK) in modulating vascular endothelial cells (VECs) in AS. High-fat feed (HFD)-induced AS rat models were prepared and treated with AMPK activator A-769662 alone or combined with chloroquine. An analysis of VEC injury, inflammation response, and autophagy followed it. The M1 linear ubiquitination of LKB1 was assessed by co-immunoprecipitation. The interaction between LKB1 and AMPK was analyzed. Primary aortic VECs were isolated and induced by LPS to verify the effects of LKB1 and AMPK on VEC injury in AS. Activation of AMPK reduced the VEC injury and inflammatory response of VECs and promoted autophagy caused by AS. LKB1 could regulate the activation of AMPK in AS. M1 linear ubiquitination enhanced LKB1 activity and increased AMPK activation to protect against VEC injury in AS, which was validated by in vitro experiments. Our current study highlighted that M1 linear ubiquitination of LKB1 may induce the activation of LKB1 to activate AMPK, which inhibited VEC injury in AS.

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Acknowledgements

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Funding

This study was funded by Basic research in Bao'an District, Shenzhen in 2021 (medical and health) (No. 2021JD301), Scientific Research Project of Guangdong Administration of Traditional Chinese Medicine (No. 20222197), and The research Project of Luohu District soft science (No. LX202202041).

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Authors and Affiliations

  1. Department of Cardiology, Shenzhen Hospital of Shanghai University of Traditional Chinese Medicine, No. 16, Xiantong Road, Liantang Street, Luohu District, Shenzhen, 518004, Guangdong, People’s Republic of China

    Haiquan Huangfu, Zhichao Huang, Weiqian Liao, Xiaoming Shang & Hairui Yu

  2. Department of Encephalopathy, Shenzhen Hospital of Shanghai University of Traditional Chinese Medicine, Shenzhen, 518004, People’s Republic of China

    Tianyu Zou

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  1. Haiquan Huangfu
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  2. Zhichao Huang
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  5. Xiaoming Shang
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Contributions

HH: conceptualization, validation, writing—original draft, and writing—review and editing; ZH: investigation, visualization, and writing—original draft; WL: Formal analysis, software, and writing—original draft; TZ: methodology, data curation, and writing—original draft; XS: conceptualization, resources, supervision, and writing—review and editing; HY: conceptualization, project administration, and writing—review and editing.

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Correspondence to Xiaoming Shang or Hairui Yu.

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The animal study was conducted following the protocol approved by our hospital (Approved No. 2022-0415) and following the National Institutes of Health guidelines.

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Huangfu, H., Huang, Z., Liao, W. et al. M1 linear ubiquitination of LKB1 inhibits vascular endothelial cell injury in atherosclerosis through activation of AMPK. Human Cell 36, 1901–1914 (2023). https://doi.org/10.1007/s13577-023-00950-2

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