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.
Original language | English (US) |
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Pages (from-to) | 138-150 |
Number of pages | 13 |
Journal | EBioMedicine |
Volume | 11 |
DOIs | |
State | Published - Sep 1 2016 |
Keywords
- Diabetic retinopathy
- Dyslipidemias
- Sphingolipids
- Vascular system injuries
- microRNA
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology