The Long Non-Coding RNA HOTAIR Is a Critical Epigenetic Mediator of Angiogenesis in Diabetic Retinopathy

Abstract

PURPOSE. Diabetic retinopathy (DR) remains a pressing issue worldwide. Abnormal angiogenesis is a distinct vascular lesion in DR, and research has established that vascular endothelial growth factor A (VEGF-A) is a primary mediator of such changes. However, limitations in current anti-VEGF therapies suggest that our understanding of molecular networks underlying ocular angiogenesis remains far from complete. Based on our long non-coding RNA (lncRNA) array analyses, HOX antisense intergenic RNA (HOTAIR) was identified as one of the top upregulated lncRNAs in high glucose-cultured human retinal endothelial cells (HRECs). Given the well-documented roles of HOTAIR in cancer, no studies have examined the epigenetic implications of HOTAIR in DR, and we investigated such relationships herein. METHODS.We used HRECs exposed to various glucose concentrations and epigenetic modulators to examine HOTAIR, angiogenic, and DR-related molecular markers. Oxidative stress, angiogenesis, and mitochondrial dysfunction were assessed. Retinal tissues of diabetic rodents and the vitreous humor and serum of patients with proliferative DR were also investigated. RESULTS.Hyperglycemia significantly augmented HOTAIR expression in HRECs and promoted angiogenesis, oxidative damage, and mitochondrial aberrations. Similarly, vitreous humor and serum from proliferative DR patients and retinas from diabetic animals demonstrated increased HOTAIR expression compared to non-diabetic controls. HOTAIR knockdown protected against glucose-induced increases of angiogenic and diabetesassociated molecules in the retina. Mechanistically, we showed that HOTAIR exerts its capabilities by preventing oxidative stress and modulating epigenetic pathways involving histone methylation, histone acetylation, DNA methylation, and transcription factors. CONCLUSIONS.Our findings suggest that HOTAIR is a critical lncRNA in the pathogenesis of DR and may potentially be important for diagnostic and therapeutic targeting.

miRNA, lncRNA and circRNA: Targeted Molecules Full of Therapeutic Prospects in the Development of Diabetic Retinopathy

“…Research (78) discovered that under HG conditions, the expression of lncRNA HOTAIR in the cytoplasm and nucleus of RPE increased. After inhibiting its expression, the expression of a variety of transcripts related to angiogenesis (VEGF-A, ET-1, ANGPTL4, PGF, HIF-1a) and epigenetic regulation (EZH2, SUZ12, DNMT1, DNMT3A, DNMT3B, CTCF, P300) was downregulated, which improved cell survival.…”

Role of Long Non-Coding RNAs and the Molecular Mechanisms Involved in Insulin Resistance

“…Similarly, HOTAIR overexpression was found in human retinal endothelial cells (HRECs) exposed to high doses of glucose. In addition, HOTAIR was localized in both the nucleus and perinuclear/cytosolic regions [ 108 ].…”

Epigenetic Regulation of the Vascular Endothelium by Angiogenic LncRNAs

“…We will highlight some of the most extensively studied lncRNAs: MALAT1, MEG3 and ANRIL. A summary of these as well as other more recently published disease-associated angiogenic lncRNAs can be seen in Table 4 (Zhou et al, 2016;Li Y. et al, 2017;Ruan et al, 2018;Niu et al, 2020;Zhang H. et al, 2020;Biswas et al, 2021).…”