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Cinnamaldehyde accelerates wound healing by promoting angiogenesis via up-regulation of PI3K and MAPK signaling pathways

Laboratory Investigationvolume 98pages783798 (2018) | Download Citation

Abstract

The bark of Cinnamomum cassia (C. cassia) has been used for the management of coronary heart disease (CHD) and diabetes mellitus. C. cassia may target the vasculature, as it stimulates angiogenesis, promotes blood circulation and wound healing. However, the active components and working mechanisms of C. cassia are not fully elucidated. The Shexiang Baoxin pill (SBP), which consists of seven medicinal materials, including C. cassia etc., is widely used as a traditional Chinese patent medicine for the treatment of CHD. Here, 22 single effective components of SBP were evaluated against the human umbilical vein endothelial cells (HUVECs). We demonstrated that in HUVECs, cinnamaldehyde (CA) stimulated proliferation, migration, and tube formation. CA also activated the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Furthermore, the secretion of vascular endothelial growth factor (VEGF) from HUVECs was increased by CA. In vivo, CA partially restored intersegmental vessels in zebrafish pretreated with PTK787, which is a selective inhibitor for vascular endothelial growth factor receptor (VEGFR). CA also showed pro-angiogenic efficacy in the Matrigel plug assay. Additionally, CA attenuated wound sizes in a cutaneous wound model, and elevated VEGF protein and CD31-positive vascular density at the margin of these wounds. These results illustrate that CA accelerates wound healing by inducing angiogenesis in the wound area. The potential mechanism involves activation of the PI3K/AKT and MAPK signaling pathways. Such a small non-peptide molecule may have clinical applications for promoting therapeutic angiogenesis in chronic diabetic wounds and myocardial infarction.

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Acknowledgements

The work was supported by program NCET Foundation, NSFC (81602980, 81473327, 81230090), partially supported by Global Research Network for Medicinal Plants (GRNMP), King Saud University, Shanghai Leading Academic Discipline Project (B906), Key laboratory of drug research for special environments, PLA, Shanghai Engineering Research Center for the Preparation of Bioactive Natural Products (10DZ2251300), the Scientific Foundation of Shanghai China (12401900801, 13401900101), National Major Project of China (2011ZX09307-002-03), the National Key Technology R&D Program of China (2012BAI29B06), and a grant to Department of Pharmacology, University of Cambridge by Shanghai Hutchison Pharmaceuticals Limited.

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Author notes

  1. These authors contributed equally: Xing Yuan, Lin Han.

Affiliations

  1. School of Pharmacy, Second Military Medical University, Shanghai, 200433, P.R. China

    • Xing Yuan
    • , Lin Han
    • , Huawu Zeng
    • , Chao Lv
    • , Wanlin Chang
    • , Weidong Zhang
    •  & Runhui Liu
  2. Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, 200433, P.R. China

    • Peng Fu
  3. Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK

    • R. Scott Runyon
    • , Momoko Ishii
    •  & Taiping Fan
  4. Biology Institute, Shandong Academy of Sciences, Jinan, 250014, P.R. China

    • Liwen Han
    •  & Kechun Liu
  5. Institute of Interdisciplinary Research Complex, Shanghai University of Traditional Chinese Medicine, Shanghai, 200040, P.R. China

    • Weidong Zhang

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The authors declare that they have no conflict of interest.

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Correspondence to Taiping Fan or Weidong Zhang or Runhui Liu.

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https://doi.org/10.1038/s41374-018-0025-8