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KPNA2 Silencing, Regulated by E3 Ubiquitin Ligase FBXW7, Alleviates Endothelial Dysfunction and Inflammation Through Inhibiting the Nuclear Translocation of p65 and IRF3: A Possible Therapeutic Approach for Atherosclerosis

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Abstract

Atherosclerosis (AS), characterized by a maladaptive inflammatory response, is one of the most common causes of death among the elderly. Karyopherin subunit alpha 2 (KPNA2), a member of the nuclear transport protein family, has been reported to play a pro-inflammatory role in various pathological processes by regulating the nuclear translocation of pro-inflammatory transcription factors. However, the function of KPNA2 in AS remains unknown. ApoE−/− mice were fed high-fat diets for 12 weeks to establish an AS mice model. Human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) to establish an AS cell model. We found that KPNA2 was upregulated in the aortic roots of atherosclerotic mice and LPS-stimulated cells. KPNA2 knockdown inhibited LPS-induced secretion of pro-inflammatory factors and monocyte-endothelial adhesion in HUVECs, whereas KPNA2 overexpression exerted the opposite effects. p65 and interferon regulatory factor 3 (IRF3), the transcription factors known to regulate the transcription of pro-inflammatory genes, interacted with KPNA2, and their nuclear translocations were blocked following KPNA2 silencing. Furthermore, we found that KPNA2 protein level was decreased by E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBXW7), which was downregulated in the atherosclerotic mice. FBXW7 overexpression induced ubiquitination with subsequent proteasomal degradation of KPNA2. Meanwhile, the effects of KPNA2 deficiency on atherosclerotic lesions were further confirmed by in vivo experiments. Taken together, our study indicates that KPNA2 downregulation, regulated by FBXW7, may alleviate endothelial dysfunction and related inflammation in the progression of AS by suppressing the nuclear translocation of p65 and IRF3.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This study was funded by the 345 Talent Project in Shengjing Hospital of China Medical University.

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Author notes

  1. Zeyu Xing and Yanhua Zhen contributed equally.

Authors and Affiliations

  1. Department of Radiology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang, 110022, Liaoning, People’s Republic of China

    Zeyu Xing, Yanhua Zhen, Jie Chen, Mingyang Du, Dongdong Li, Ruyin Liu & Jiahe Zheng

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  1. Zeyu Xing
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  2. Yanhua Zhen
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Contributions

Z. X. and Y. Z. conceptualization; Z. X., Y. Z., and J. C. methodology; Z. X., Y. Z., and M. D. investigation; Z. X., Y. Z., D. L., and R. L. data curation; Z. X. and Y. Z. writing-original draft; J. Z. writing—reviewing and editing; J. Z. supervision.

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Correspondence to Jiahe Zheng.

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This study was performed according to guidelines provided by the Animal Care Use Committee of Shengjing Hospital of China Medical University (No: 2022PS813K) and was approved by the committee.

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Xing, Z., Zhen, Y., Chen, J. et al. KPNA2 Silencing, Regulated by E3 Ubiquitin Ligase FBXW7, Alleviates Endothelial Dysfunction and Inflammation Through Inhibiting the Nuclear Translocation of p65 and IRF3: A Possible Therapeutic Approach for Atherosclerosis. Inflammation 46, 2071–2088 (2023). https://doi.org/10.1007/s10753-023-01863-w

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