MicroRNA-126 contributes to Niaspan treatment induced vascular restoration after diabetic retinopathy

Wang, Yang; Yan, Hua

doi:10.1038/srep26909

Cited by 31 publications

(24 citation statements)

References 45 publications

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“…The miR-126 was shown to inhibit the expression of VEGF and MMP-9, both important in DR [27] . The downregulation of miR-126 could induce endothelial injury and participate in the development and progression of diabetic vascular complications [28][29][30] . Although the miR-146 (with MRE of hsa_circRNA_100192) expression level was elevated in the retina of streptomycin-induced diabetic rats [26] , further reports showed it was downregulated in the vitreous fluid of diabetic patients [31] .…”

Section: Discussionmentioning

confidence: 99%

Altered Expression Profile of Circular RNAs in the Serum of Patients with Diabetic Retinopathy Revealed by Microarray

Wang

et al. 2017

Ophthalmic Res

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Purpose: Diabetic retinopathy (DR) is the leading cause of blindness among working age adults. Circular RNAs (circRNAs) are a kind of noncoding RNAs that are involved in the development of some diseases. Here, we aimed to determine the possible role of circRNAs in the pathogenesis of DR by determining the expression profile of circRNAs in the serum of DR patients. Methods: Nineteen subjects with type 2 diabetes mellitus with proliferative DR (T2DR), 15 subjects with type 2 diabetes mellitus without DR (T2DM), and 21 age-matched nondiabetic control subjects were included in the study. Expression profiles in the serum samples from 5 subjects of each group were studied by circular microarray and validated by quantitative real-time polymerase chain re- action (qRT-PCR) in another 40 subjects. Bioinformatic software was used to predict the microRNA response elements. Results: Thirty circRNAs were significantly upregulated in the serum of T2DR patients compared with the serum from both T2DM and control patients. Further, the altered expression of 7 circRNAs (hsa_circRNA_063981, hsa_circRNA_ 404457, hsa_circRNA_100750, hsa_circRNA_406918, hsa_ circRNA_104387, hsa_circRNA_103410, and hsa_circRNA_ 100192) were verified by qRT-PCR. Conclusion: This study suggested a potential role of circRNAs in the pathogenesis of DR and provides novel molecular targets for clinical therapy.

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Section: Discussionmentioning

confidence: 99%

Altered Expression Profile of Circular RNAs in the Serum of Patients with Diabetic Retinopathy Revealed by Microarray

Wang

et al. 2017

Ophthalmic Res

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“…Both miR-152 (Haque et al, 2015) and miR-200b (Jiang et al, 2015) suppressed VEGF expression in human REC under high glucose conditions. In addition, a negative correlation of miR-126 with VEGF signaling was found in the retinas of STZ-induced diabetic rats (Wang & Yan, 2016) and topical delivery of miR-106a mimic reduced VEGF levels in the retina of STZ-diabetic mice (Ling et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins

Liu

Steinle

2017

Vision Research

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Hyperglycemia is a significant risk factor for diabetic retinopathy and induces multiple biochemical changes, including inflammation and endothelial dysfunction in the retina. Alterations in microRNA expression have been implicated in the pathological responses of diabetic retinopathy and the manipulation of microRNA may provide powerful strategy for therapeutics. Among the predicted targets of miR-15a and -16 are TGF-beta3, SMAD2/3, and VEGF, all of which are known to play a role in vascular endothelial functions. The purpose of this study was to investigate the hypothesis that miR-15a/16 inhibits TGF-beta3/VEGF signaling to maintain retinal endothelial cell barrier protein levels. Human primary retinal endothelial cells (REC) were maintained in normal (5 mM) glucose or transferred to high glucose medium (25 mM) for 3 days. REC were transfected with miRNA mimics (hsa-miR-15a-5p and -16-5p). Retinal lysates from miR-15a-transgenic mice were also analyzed. We demonstrated that overexpression of miR-15a/16 resulted in decreased TGF-beta3 signaling and VEGF levels in cultured REC grown in high glucose conditions. In addition, the levels of tight junction proteins, zonula occludens-1 (ZO-1) and occludin, were elevated in REC following overexpression of miR-15a and -16. Overexpression of miR-15a and - 16 played a role in reducing cellular permeability through inhibition of VEGF signaling in REC cultured under high glucose conditions. Using miR-15a-transgenic mice, we demonstrated the regulatory role of miR-15a on TGF-beta3 signaling and tight junction proteins in vivo. Our outcomes suggest that miR-15a/16 maintain the retinal endothelial cell barrier by reducing TGFbeta3/VEGF signaling and increasing levels of key tight junction proteins.

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“…Niaspan treatment reversed these deleterious effects and enhanced miR-126 level. This observation indicated that miR-126 plays an important role in the Niaspan-mediated antidiabetic effect and enhances endothelial barrier by targeting tight junction protein expression [9]. In glioma ECs, upregulation of miR-181a targeted Kruppel-like factor 6 (KLF6), downregulating ZO-1, occluding, and claudin-5, and increased permeability of the blood-tumor barrier (BTB) [10].…”

Section: Tight Junction Proteinsmentioning

confidence: 99%

MicroRNA Regulation of Endothelial Junction Proteins and Clinical Consequence

Zhuang

Mastej

et al. 2016

Mediators of Inflammation

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Cellular junctions play a critical role in structural connection and signal communication between cells in various tissues. Although there are structural and functional varieties, cellular junctions include tight junctions, adherens junctions, focal adhesion junctions, and tissue specific junctions such as PECAM-1 junctions in endothelial cells (EC), desmosomes in epithelial cells, and hemidesmosomes in EC. Cellular junction dysfunction and deterioration are indicative of clinical diseases. MicroRNAs (miRNA) are ~20 nucleotide, noncoding RNAs that play an important role in posttranscriptional regulation for almost all genes. Unsurprisingly, miRNAs regulate junction protein gene expression and control junction structure integrity. In contrast, abnormal miRNA regulation of junction protein gene expression results in abnormal junction structure, causing related diseases. The major components of tight junctions include zonula occluden-1 (ZO-1), claudin-1, claudin-5, and occludin. The miRNA regulation of ZO-1 has been intensively investigated. ZO-1 and other tight junction proteins such as claudin-5 and occludin were positively regulated by miR-126, miR-107, and miR21 in different models. In contrast, ZO-1, claudin-5, and occludin were negatively regulated by miR-181a, miR-98, and miR150. Abnormal tight junction miRNA regulation accompanies cerebral middle artery ischemia, brain trauma, glioma metastasis, and so forth. The major components of adherens junctions include VE-cadherin, β-catenin, plakoglobin, P120, and vinculin. VE-cadherin and β-catenin were regulated by miR-9, miR-99b, miR-181a, and so forth. These regulations directly affect VE-cadherin-β-catenin complex stability and further affect embryo and tumor angiogenesis, vascular development, and so forth. miR-155 and miR-126 have been shown to regulate PECAM-1 and affect neutrophil rolling and EC junction integrity. In focal adhesion junctions, the major components are integrin β4, paxillin, and focal adhesion kinase (FAK). Integrin β4 has been regulated by miR-184, miR-205, and miR-9. Paxillin has been regulated by miR-137, miR-145, and miR-218 in different models. FAK has been regulated by miR-7, miR-138, and miR-135. Deregulation of miRNAs is caused by viral infections, tumorigenesis, and so forth. By regulation of posttranscription, miRNAs manipulate junction protein expression in all cellular processes and further determine cellular fate and development. Elucidation of these regulatory mechanisms will become a new alternative therapy for many diseases, such as cancers and inflammatory diseases.

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MicroRNA-126 contributes to Niaspan treatment induced vascular restoration after diabetic retinopathy

Cited by 31 publications

References 45 publications

Altered Expression Profile of Circular RNAs in the Serum of Patients with Diabetic Retinopathy Revealed by Microarray

Altered Expression Profile of Circular RNAs in the Serum of Patients with Diabetic Retinopathy Revealed by Microarray

miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins

MicroRNA Regulation of Endothelial Junction Proteins and Clinical Consequence

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