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GDF-15 promotes angiogenesis through modulating p53/HIF-1α signaling pathway in hypoxic human umbilical vein endothelial cells

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Abstract

Angiogenesis is an important repair mechanism in response to ischemia/reperfusion (I/R) injury through increasing blood flow and oxygen supply. Previous studies suggested that growth differentiation factor 15 (GDF-15) was one of the most important factors responsible for promoting the angiogenesis process during cardiac ischemia. Here we tested the hypothesis that GDF-15 could promote angiogenesis via HIF-1α/VEGF dependent signaling pathway. Impaired angiogenic response was significantly improved, VEGF expression up-regulated and p53 inhibited by GDF-15 in hypoxic human umbilical vein endothelial cells (HUVECs). Expression of hypoxia-inducible factor 1-alpha (HIF-1α), an important transcriptional factor linked with angiogenesis, was significantly down-regulated post 24 h hypoxia, HIF-1α expression could be significantly up-regulated and HIF-1α nuclear translocation significantly enhanced by pretreatment with GDF-15 in hypoxic HUVECs. Knock-down HIF-1α by small interference RNA (siRNA) abolished GDF-15-mediated angiogenic effect and suppressed VEGF expression. Further experiments showed that GDF-15 activated HIF-1α signal via stabilizing p53-MDM2 complex and MDM2-mediated p53 ubiquitylation. Nutlin-3, an Hdm2 antagonist, promoted p53 nuclear translocation and attenuated GDF-15-induced activation of HIF-1α and downstream VEGF signaling in hypoxic HUVECs. Taken together, our results suggested that GDF-15 promoted angiogenesis in hypoxic HUVECs possibly through inhibiting p53 signal, which subsequently enhanced and stabolized HIF-1α expression, and up-regulated the related downstream angiogenic signaling.

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Acknowledgment

We thank Dr. Chenxing Shen from Xinhua Hospital, JiaoTong University for his help in the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, People’s Republic of China

    Hejian Song & Zhihua Liu

  2. The First People’s Hospital of Lianyungang City, 222002, Jiangsu, People’s Republic of China

    Delu Yin

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  1. Hejian Song
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  2. Delu Yin
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  3. Zhihua Liu
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Correspondence to Hejian Song.

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Song, H., Yin, D. & Liu, Z. GDF-15 promotes angiogenesis through modulating p53/HIF-1α signaling pathway in hypoxic human umbilical vein endothelial cells. Mol Biol Rep 39, 4017–4022 (2012). https://doi.org/10.1007/s11033-011-1182-7

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  • DOI: https://doi.org/10.1007/s11033-011-1182-7

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