Abstract
In this study, we investigated the role of a long non-coding RNA GAPLINC in angiogenesis using human umbilical vein endothelial cells (HUVEC). We found that hypoxia and hypoxia-inducible factor 1α (HIF-1α) increased the expression of GAPLINC in HUVEC cells. Moreover, GAPLINC overexpression down-regulated miR-211 and up-regulated Bcl2 protein expression. Further rescue experiments confirmed that hypoxia directly increased GAPLINC expression. GAPLINC overexpression also increased cell migration and vessel formation which promoted angiogenesis, and these changes were attributed to the increased expression of vascular endothelial growth factor receptors (VEGFR) and delta-like canonical notch ligand 4 (DLL4) receptors. Finally, we demonstrated that GAPLINC promotes vessel formation and migration by regulating MAPK and NF-kB signalling pathways. Taken together, these findings comprehensively demonstrate that overexpression of GAPLINC increases HUVEC cells angiogenesis under hypoxia condition suggesting that GAPLINC can be a potential target for critical limb ischaemia (CLI) treatment.
Keywords:
Bcl2; GAPLINC; angiogenesis; critical limb ischaemia; hypoxia; long non-coding RNA; miR-211.
© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Calcium-Binding Proteins / metabolism
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Cell Hypoxia
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Cell Movement / genetics
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Databases, Genetic
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Down-Regulation
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Gene Expression Regulation / genetics*
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Human Umbilical Vein Endothelial Cells
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Humans
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Ischemia / genetics
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Ischemia / metabolism*
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MAP Kinase Signaling System / genetics
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Mixed Function Oxygenases / genetics
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Mixed Function Oxygenases / metabolism
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NF-kappa B / metabolism
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Long Noncoding / genetics
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RNA, Long Noncoding / metabolism*
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RNA, Small Interfering
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Umbilical Veins / metabolism*
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Umbilical Veins / pathology
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Up-Regulation
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Calcium-Binding Proteins
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DLL4 protein, human
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MIRN211 microRNA, human
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MicroRNAs
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NF-kappa B
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Proto-Oncogene Proteins c-bcl-2
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RNA, Long Noncoding
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RNA, Small Interfering
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Repressor Proteins
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Mixed Function Oxygenases
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HIF1AN protein, human
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KDR protein, human
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Receptors, Vascular Endothelial Growth Factor
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Vascular Endothelial Growth Factor Receptor-2