title: Hypoxia induces the proliferation of endothelial progenitor cells via upregulation of Apelin/APLNR/MAPK signaling.
abstract: Endothelial progenitor cells (EPCs) can form new vessels through differentiation into endothelial cells (ECs), thus being important in the prevention of hypoxia/ischemia. Apelin can activate different signaling pathways through its receptor, APLNR, which regulate diverse biological functions, including cardiovascular function. However, the molecular mechanism by which Apelin mediates hypoxia-induced EPCs proliferation remain to be fully elucidated. The present study aimed to determine the role of Apelin/APLNR signaling in hypoxia-induced proliferation of EPCs. MTT assay was used to determine cell proliferation. Reverse transcription-quantitative polymerase chain reaction and western blotting analysis were conducted to examine mRNA and protein expression. It was revealed that hypoxia promoted the proliferation of the EPCs. Further investigation demonstrated that hypoxia promoted the expression levels of hypoxia-inducible factor (HIF)-1α, Apelin and APLNR in the EPCs. In addition, upregulation of Apelin or APLNR promoted the hypoxia-induced proliferation of the EPCs, while knockdown of Apelin or APLNR by small interfering RNA suppressed the hypoxia-induced proliferation of the EPCs, suggesting that the Apelin/APLNR axis is involved in hypoxia-induced proliferation of EPCs. Furthermore, pretreatment of the EPCs with SB-239063 or PD98059, two inhibitors of mitogen-activated protein kinase (MAPK), eliminated the Apelin upregulation-induced EPC proliferation, suggesting that MAPK signaling is a downstream effecter of Apelin/APLNR in EPCs. Therefore, the findings of the present study indicated that the production of HIF-1α, induced by hypoxia, activated the Apelin/APLNR and the downstream MAPK signaling pathways, leading to upregulated proliferation of the EPCs. These findings suggested that Apelin/APLNR signaling may be used as a potential therapeutic target for hypoxic/ischemic injury.
authors.affiliation: Department of Cardiology, The Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China.
authors.forename: Jingchang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China.
authors.forename: Zhenfei
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China.
authors.forename: Xinqun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410000, P.R. China.
authors.forename: Shenghua
authors.initials: S
authors.lastname: Zhou
mesh_terms: D000073861:Apelin; D000075244:Apelin Receptors; D015687:Cell Hypoxia; D049109:Cell Proliferation; D066026:Endothelial Progenitor Cells / Q000166:cytology* / Q000201:enzymology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled