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

Qi Wang, Svetlana Navitskaya, Harshini Chakravarthy, Chao Huang, Nermin Kady, Todd A. Lydic, Y. Eugene Chen, Ke Jie Yin, Folami Lamoke Powell, Pamela M. Martin, Maria B. Grant, Julia V. Busik

Research output: Contribution to journalArticle

37 Scopus citations

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 languageEnglish (US)
Pages (from-to)138-150
Number of pages13
JournalEBioMedicine
Volume11
DOIs
StatePublished - Sep 1 2016

Keywords

  • Diabetic retinopathy
  • Dyslipidemias
  • Sphingolipids
  • Vascular system injuries
  • microRNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wang, Q., Navitskaya, S., Chakravarthy, H., Huang, C., Kady, N., Lydic, T. A., Chen, Y. E., Yin, K. J., Powell, F. L., Martin, P. M., Grant, M. B., & Busik, J. V. (2016). Dual Anti-Inflammatory and Anti-Angiogenic Action of miR-15a in Diabetic Retinopathy. EBioMedicine, 11, 138-150. https://doi.org/10.1016/j.ebiom.2016.08.013