title: GDF-15 promotes angiogenesis through modulating p53/HIF-1α signaling pathway in hypoxic human umbilical vein endothelial cells.
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.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, People's Republic of China. hjsong660758@126.com
authors.forename: Hejian
authors.initials: H
authors.lastname: Song
authors.forename: Delu
authors.initials: D
authors.lastname: Yin
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000378:metabolism / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2