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β-elemene affects angiogenesis of infantile hemangioma by regulating angiotensin-converting enzyme 2 and hypoxia-inducible factor-1 alpha

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Abstract

Infantile hemangioma (IH) is the most common benign vascular tumor resulting from the hyper-proliferation of vascular endothelial cells. In treatment of various tumors including IH, β-elemene, a compound extracted from Rhizoma zedoariae, has been reported to have anti-tumor effect. However, the underlying mechanisms of β-elemene in hemangioma have remained uninvestigated. In this presented study, functional analysis showed that low concentrations of β-elemene promoted the proliferation, migration and tube formation of human hemangioma endothelial cells (HemECs), while high concentrations of β-elemene produced inhibitory effects. Further, we also found that angiotensin-converting enzyme 2 (ACE2) expression was down-regulated at both mRNA and protein levels, while hypoxia-inducible factor-1 alpha (HIF-1-α) was up-regulated in infantile hemangiomas tissues and HemECs at both mRNA and protein levels. This result suggested that ACE2 and HIF-1-α play roles in IH. ACE2 expression was down-regulated with the treatment of β-elemene at different dosage point. Interestingly, the expression of Vascular endothelial growth factor-A (VEGFA) increased with treatment of low concentrations of β-elemene in HemECs, in contrary, the expression of VEGFA expression decreased with treatment of high concentrations of β-elemene. Moreover, if the concentration of β-elemene reached 40 μg/ml or higher, the expression of HIF-1-α decreased. Taken together, our data indicated that the different effects of β-elemene on the proliferation, migration and angiogenesis of hemangioma at different concentrations: The ACE2 signaling pathway dominates with treatment of low concentrations of β-elemene, stimulating the expression of downstream VEGFA to promote the angiogenesis of hemangioma; under the condition of high concentrations of β-elemene, the HIF-1-α signaling pathway inhibits the expression of VEGFA and further inhibits the angiogenesis of hemangioma.

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Acknowledgements

The authors did not receive support from any organization for the submitted work.

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Author notes

  1. Zhenyu Wang, Zhaoxiang Wang and Chenyu Du contributed equally.

Authors and Affiliations

  1. Department of Pediatric Surgery, Affiliated Hospital of Nantong University, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China

    Zhenyu Wang & Hua Xian

  2. Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong University, Jiangsu, 226001, China

    Zhaoxiang Wang

  3. Department of Physiology, School of Medicine, Nantong University, Jiangsu, 226001, China

    Chenyu Du

  4. Laboratory of Medical Science, School of Medicine, Nantong University, Jiangsu, 226001, China

    Ye Zhang & Baorui Tao

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  1. Zhenyu Wang
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  2. Zhaoxiang Wang
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  4. Ye Zhang
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Correspondence to Hua Xian.

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Wang, Z., Wang, Z., Du, C. et al. β-elemene affects angiogenesis of infantile hemangioma by regulating angiotensin-converting enzyme 2 and hypoxia-inducible factor-1 alpha. J Nat Med 75, 655–663 (2021). https://doi.org/10.1007/s11418-021-01516-y

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  • DOI: https://doi.org/10.1007/s11418-021-01516-y

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