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.
Highlights
Critical limb ischaemia (CLI) is a clinical syndrome of ischaemia pain, rest pain, ischaemic ulceration and gangrene with a high risk of limb loss, cardiovascular disease and major amputation
We performed Gene Set Enrichment Analysis (GSEA), and the results showed that GPCR (G‐protein‐cou‐ pled receptors) pathway and TGF‐β pathway were down‐regulated in CLI patient
Since the GAPLINC can influence the cell migration and vessel for‐ mation in human umbilical vein endothelial cells (HUVEC) cells, we explored the possibility that delta‐like canonical notch ligand 4 (DLL4) and vascular endothelial growth factor receptors (VEGFR) pathway may involved in these phenotypes
Summary
Critical limb ischaemia (CLI) is a clinical syndrome of ischaemia pain, rest pain, ischaemic ulceration and gangrene with a high risk of limb loss, cardiovascular disease and major amputation. LncRNA can manipulate target proteins previously considered to be undruggable They can be targeted with higher specificity than other small molecules.[13] For instance, the re‐ cently identified GAPLINC is a 924‐bp lncRNA, that is involved in different types of cancer.[14,15,16,17] In gastric cancer and colorectal cancer, GAPLINC competes with CD44 for miR‐211, and higher expression of GAPLINC was found to be correlated with large tumour size.[14] High expression of GAPLINC increases cell migration and vessel for‐ mation. We aimed at understanding the molecular mechanism of angiogenesis under hypoxia condition and aimed to identify novel therapies for CLI based on lncRNAs
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