Dual Anti-Inflammatory and Anti-Angiogenic Action of miR-15a in Diabetic Retinopathy

• Published in: EBioMedicine Vol. 11; no. C; pp. 138 - 150
• Main Authors: Wang, Qi, Navitskaya, Svetlana, Chakravarthy, Harshini, Huang, Chao, Kady, Nermin, Lydic, Todd A., Chen, Y. Eugene, Yin, Ke-Jie, Powell, Folami Lamoke, Martin, Pamela M., Grant, Maria B., Busik, Julia V.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2016; Elsevier
• Subjects: 3' Untranslated Regions; Advanced Basic Science; Animals; Cell Movement - genetics; Cells, Cultured; Ceramides - biosynthesis; Diabetes Mellitus, Experimental; Diabetic retinopathy; Diabetic Retinopathy - genetics; Diabetic Retinopathy - metabolism; Diabetic Retinopathy - pathology; Disease Models, Animal; Dyslipidemias; Endothelial Cells; Gene Expression Profiling; Gene Expression Regulation; Humans; Internal Medicine; Male; Mice; microRNA; MicroRNAs - genetics; Neovascularization, Pathologic - genetics; Rats; Research Paper; Retina - metabolism; Retinal Pigment Epithelium - cytology; Retinal Pigment Epithelium - metabolism; Retinal Vessels; RNA Interference; Sphingolipids; Sphingomyelin Phosphodiesterase - genetics; Sphingomyelin Phosphodiesterase - metabolism; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular system injuries; Diabetic retinopathy; Vascular system injuries; microRNA; Sphingolipids; Dyslipidemias
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.08.013

Activation of pro-inflammatory and pro-angiogenic pathways in the retina and the bone marrow contributes to pathogenesis of diabetic retinopathy. We identified miR-15a as key regulator of both pro-inflammatory and pro-angiogenic pathways through direct binding and inhibition of the central enzyme in the sphingolipid metabolism, ASM, and the pro-angiogenic growth factor, VEGF-A. miR-15a was downregulated in diabetic retina and bone marrow cells. Over-expression of miR-15a downregulated, and inhibition of miR-15a upregulated ASM and VEGF-A expression in retinal cells. In addition to retinal effects, migration and retinal vascular repair function was impaired in miR-15a inhibitor-treated circulating angiogenic cells (CAC). Diabetic mice overexpressing miR-15a under Tie-2 promoter had normalized retinal permeability compared to wild type littermates. Importantly, miR-15a overexpression led to modulation toward nondiabetic levels, rather than complete inhibition of ASM and VEGF-A providing therapeutic effect without detrimental consequences of ASM and VEGF-A deficiencies.