Rationale: Angiotensin II (AngII)-mediated vascular smooth muscle cell (VSMC) dysfunction plays a major role in hypertension. Long non-coding RNAs (lncRNAs) have elicited much interest, but their molecular roles in AngII actions and hypertension are unclear. Objective: To investigate the regulation and functions of a novel lncRNA “Growth factor- and pro-Inflammatory cytokine-induced Vascular cell-Expressed RNA (Giver)”, in AngII-mediated VSMC dysfunction. Methods and Results: RNA-sequencing and RT-qPCRs revealed that treatment of rat VSMC with AngII increased the expression of Giver and Nr4a3, an adjacent gene encoding a nuclear receptor. Similar changes were observed in rat and mouse aortas treated ex vivo with AngII. RNA-FISH and subcellular fractionation showed predominantly nuclear localization of Giver. AngII increased Giver expression via recruitment of Nr4a3 to Giver promoter. Microarray profiling and RT-qPCR validation in VSMC showed that Giver knockdown attenuated the expression of genes involved in oxidative stress (Nox1) and inflammation (Il6, Ccl2, Tnf), but increased Nr4a3. Conversely, endogenous Giver overexpression showed opposite effects supporting its role in oxidative stress and inflammation. ChIP assays showed Giver overexpression also increased RNA-polymerase II (Pol II) enrichment and decreased repressive histone modification H3K27me3 at Nox1 and inflammatory gene promoters. Accordingly, Giver knockdown inhibited AngII-induced oxidative stress and proliferation in rat VSMC. RNA pull-down combined with mass-spectrometry showed Giver interacts with nuclear and chromatin remodeling proteins, and corepressors including NONO. Moreover, NONO knockdown elicited similar effects as Giver knockdown on the expression of key Giver-regulated genes. Notably, GIVER and NR4A3 were increased in AngII treated human VSMC, and in arteries from hypertensive patients, but attenuated in hypertensive patients treated with Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers. Furthermore, human GIVER also exhibits partial functional conservation with rat Giver. Conclusions: Giver and its regulator Nr4a3 are important players in AngII-mediated VSMC dysfunction and could be novel targets for anti-hypertensive therapy.

BackgroundLong noncoding RNAs (lncRNAs) have recently received wide attention as key molecules that mediate a variety of physiological and pathological processes by regulating gene expression; however, knowledge of lncRNAs in rheumatoid arthritis (RA) is limited. Thus, we investigated the lncRNA expression profile in fibroblast-like synoviocytes (FLSs) from patients with RA and explored the function of abundantly expressed lncRNAs.MethodsLncRNA and mRNA microarrays were performed to identify differentially expressed lncRNAs in RA FLSs compared with normal FLSs. Quantitative polymerase chain reaction (qPCR) was used to validate the results, and correlation analysis was used to analyze the relationship between these aberrantly expressed lncRNAs and clinical characteristics. A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic value of the lncRNAs identified.ResultsAccording to the gene expression profiles, 135 lncRNAs were differentially expressed between RA and normal FLSs. Furthermore, qPCR data showed that lncRNA ENST00000483588 was up-regulated and that three lncRNAs (ENST00000438399, uc004afb.1, and ENST00000452247) were down-regulated in RA FLSs. The expression level of ENST00000483588 was positively correlated with the level of C-reactive protein and the Simplified Disease Activity Index score. Moreover, the areas under the ROC curve were 0.85, 0.92, 0.97, and 0.92 for ENST00000483588, ENST00000438399, uc004afb.1, and ENST00000452247, respectively.ConclusionsThe results indicate that the dysregulation of ENST00000483588, ENST00000438399, uc004afb.1, and ENST00000452247 may be involved in the pathological processes of RA and that these lncRNAs may have potential value for the diagnosis and assessment of the disease activity of RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1129-4) contains supplementary material, which is available to authorized users.

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Long noncoding RNAs play an important role in various biological processes, including tumorigenesis. FOXC1 (Forkhead box C1) is a member of the Forkhead box family of transcription factors and plays a crucial role in nasopharyngeal carcinoma. In this study, a novel long noncoding RNA (FOXCUT) located upstream of FOXC1 was investigated in 42 nasopharyngeal carcinoma patients. Our analysis revealed that the expression levels of FOXCUT and FOXC1 in nasopharyngeal carcinoma tissues were significantly higher than those observed in chronic nasopharyngitis tissues and that FOXCUT expression was positively correlated with FOXC1 expression. Additionally, knockdown of FOXCUT significantly inhibited proliferation and migration of nasopharyngeal carcinoma cell lines and resulted in downregulated expression of the matrix metalloproteinase 7 and matrix metalloproteinase 9, as well as vascular endothelial growth factor A and β-catenin. Our findings suggested that FOXCUT expression contributed to the development and progression of nasopharyngeal carcinoma by targeting FOXC1 and that FOXCUT might be useful as a potential nasopharyngeal carcinoma biomarker and therapeutic target.