LncRNA HOTAIR regulates the PI3K/AKT pathway via the miR‐126‐3p/PIK3R2 axis to participate in synovial angiogenesis in rheumatoid arthritis

BACKGROUND: The abnormal expression of long noncoding RNA (LncRNA) HOTAIR has been associated with synovial angiogenesis in rheumatoid arthritis (RA). The aim of this study is to investigate whether LncRNA HOTAIR plays a role in synovial angiogenesis in RA by regulating the phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT) pathway through the miR‐126‐3p/PIK3R2 axis. METHODS: In this study, we conducted in vitro experiments by designing overexpression plasmids and small interfering RNAs targeting LncRNA HOTAIR and then transfected them into rheumatoid arthritis fibroblast‐like synoviocytes (RA‐FLS). We then co‐cultured the RA‐FLS with human umbilical vein endothelial cells (HUVEC) to establish a RA‐FLS‐induced HUVEC model. We investigated the effects of LncRNA HOTAIR on the proliferation, migration, lumen forming ability of HUVEC, as well as the expression of synovial endothelial cell markers, angiogenic factors, and the PI3K/AKT pathway. To validate the interactions between LncRNA HOTAIR, miR‐126‐3p, and PIK3R2, we used bioinformatics and luciferase reporter experiments. We also employed real‐time fluorescence quantitative, Western blotanalysis, and immunofluorescence techniques to analyze the target genes and proteins. RESULTS: The expression of LncRNA HOTAIR was upregulated in HUVEC induced by RA‐FLS. The overexpression of LncRNA HOTAIR significantly increased the expression of vascular endothelial growth factor, basic fibroblast growth factor, CD34, and CD105 in HUVEC, promoting their proliferation, migration, and lumen formation. At the same time, the overexpression of LncRNA HOTAIR inhibited the expression of miR‐126‐3p, promoted the expression of PIK3R2, activated the PI3K/AKT pathway, and promoted the expression of PI3K, AKT and phosphorylated‐AKT, while the silence of LncRNA HOTAIR reversed these expressions. Bioinformatics and double luciferase reporter gene experiments confirmed the targeting relationship among LncRNA HOTAIR, miR‐126‐3p, and PIK3R2. Finally, the rescue experiments showed that PI3K agonists could reverse the inhibitory effect of silent LncRNA HOTAIR on HUVEC. CONCLUSION: LncRNA HOTAIR has the potential to activate the PI3K/AKT pathway, likely through the regulatory axis involving miR‐126‐3p/PIK3R2, consequently contributing to synovial angiogenesis in RA.