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LOX-1 regulation of H-type vascular endothelial cell regeneration in hyperglycemia

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Abstract

Aims

Diabetic osteoporosis (DOP) is the most common secondary form of osteoporosis. Diabetes mellitus affects bone metabolism; however, the underlying pathophysiological mechanisms remain unclear. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression is upregulated in conditions characterized by vascular injury, such as atherosclerosis, hypertension, and diabetes. Additionally, Notch, HIF-1α, and VEGF are involved in angiogenesis and bone formation. Therefore, we aimed to investigate the expression of Notch, HIF-1α, and VEGF in the LOX-1 silencing state.

Methods

Rat bone H-type vascular endothelial cells (THVECs) were isolated and cultured in vitro. Cell identification was performed using immunofluorescent co-expression of CD31 and Emcn. Lentiviral silencing vector (LV-LOX-1) targeting LOX-1 was constructed using genetic recombination technology and transfected into the cells. The experimental groups included the following: NC group, HG group, LV-LOX-1 group, LV-CON group, HG + LV-LOX-1 group, HG + LV-CON group, HG + LV-LOX-1 + FLI-06 group, HG + LV-CON + FLI-06 group, HG + LV-LOX-1 + LW6 group, and HG + LV-CON + LW6 group. The levels of LOX-1, Notch, Hif-1α, and VEGF were detected using PCR and WB techniques to investigate whether the expression of LOX-1 under high glucose conditions has a regulatory effect on downstream molecules at the gene and protein levels, as well as the specific molecular mechanisms involved.

Results

High glucose (HG) conditions led to a significant increase in LOX-1 expression, leading to inhibition of angiogenesis, whereas silencing LOX-1 can reverse this phenomenon. Further analysis reveals that changes in LOX-1 will promote changes in Notch/HIF-1α and VEGF. Moreover, Notch mediates the activation of HIF-1α and VEGF.

Conclusions

The activation of LOX-1 and the inhibition of Notch/HIF-1α/VEGF in THVECs are the main causes of DOP. These findings contribute to our understanding of the pathogenesis of DOP and offer a novel approach for preventing and treating osteoporosis.

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Data availability statement

Data will be made available on request.

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Funding

Qi Zhang was supported by National Natural Science Foundation of China [81960173], National Research Incubation Project of Gansu Provincial People's Hospital [19SYPYB-4], Lanzhou Health and Wellness Commission [2021005].

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Authors and Affiliations

  1. The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, 730000, China

    Haoyue Lei, Wenhui Guo & Youzhuo Pan

  2. School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750000, China

    Xun Lu

  3. Department of Gerontology, Gansu Provincial Hospital, Lanzhou, 730000, China

    Qi Zhang

Authors
  1. Haoyue Lei
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  2. Wenhui Guo
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  3. Youzhuo Pan
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  4. Xun Lu
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  5. Qi Zhang
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Contributions

HL conceived and designed the experiments; performed the experiments; and wrote the paper. WG; YP performed the experiments. XL analyzed and interpreted the data. QZ conceived and designed the experiments; contributed reagents, materials, analysis tools or data; and wrote the paper.

Corresponding author

Correspondence to Qi Zhang.

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Conflict of interest

We have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study.

Ethical approval

This study has obtained approval from the Medical Ethics Committee of Gansu Provincial People’s Hospital and meets the ethical requirements. The approval number for this study is 2023-066. Original approval documents have been obtained and uploaded. These declarations are made to uphold transparency, adhere to ethical standards, and ensure the credibility and integrity of the research presented.

Human or animal rights

Research involving human participants of animals: The procedures met the experimental ethics requirements of the Gansu Provincial People's Hospital.

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Lei, H., Guo, W., Pan, Y. et al. LOX-1 regulation of H-type vascular endothelial cell regeneration in hyperglycemia. Acta Diabetol 61, 515–524 (2024). https://doi.org/10.1007/s00592-023-02224-7

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  • DOI: https://doi.org/10.1007/s00592-023-02224-7

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