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

EBioMedicine. 2016 Sep:11:138-150. doi: 10.1016/j.ebiom.2016.08.013. Epub 2016 Aug 8.

Abstract

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.

Keywords: Diabetic retinopathy; Dyslipidemias; Sphingolipids; Vascular system injuries; microRNA.

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Cell Movement / genetics
  • Cells, Cultured
  • Ceramides / biosynthesis
  • Diabetes Mellitus, Experimental
  • Diabetic Retinopathy / genetics*
  • Diabetic Retinopathy / metabolism
  • Diabetic Retinopathy / pathology*
  • Disease Models, Animal
  • Endothelial Cells
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Neovascularization, Pathologic / genetics*
  • RNA Interference
  • Rats
  • Retina / metabolism
  • Retinal Pigment Epithelium / cytology
  • Retinal Pigment Epithelium / metabolism
  • Retinal Vessels
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • 3' Untranslated Regions
  • Ceramides
  • MicroRNAs
  • Mirn15a microRNA, mouse
  • Vascular Endothelial Growth Factor A
  • Sphingomyelin Phosphodiesterase