September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Targeting Acid Sphingomyelinase and Vascular Endothelial Growth Factor by miR-15a to Treat Diabetic Retinopathy
Author Affiliations & Notes
  • Julia V Busik
    Michigan State University, East Lansing, Michigan, United States
  • Svetlana N Navitskaya
    Michigan State University, East Lansing, Michigan, United States
  • Harshini Chakravarthy
    Michigan State University, East Lansing, Michigan, United States
  • Chao Huang
    Michigan State University, East Lansing, Michigan, United States
  • Nermin Kady
    Michigan State University, East Lansing, Michigan, United States
  • Todd V Lydic
    Michigan State University, East Lansing, Michigan, United States
  • Walter V Esselman
    Michigan State University, East Lansing, Michigan, United States
  • Maria B Grant
    Ophthalmology, Indiana University, Indianapolis, Indiana, United States
  • Qi Wang
    Michigan State University, East Lansing, Michigan, United States
  • Footnotes
    Commercial Relationships   Julia Busik, None; Svetlana Navitskaya, None; Harshini Chakravarthy, None; Chao Huang, None; Nermin Kady, None; Todd Lydic, None; Walter Esselman, None; Maria Grant, None; Qi Wang, None
  • Footnotes
    Support  National Institutes of Health (NIH) grant EY-01-6077, Michigan AgBioResearch grant MICL02163 to JVB, NIH grants EY-07739 and EY-12601 to MBG, and NIH grant DK-09-0730 to MBG and JVB, Jean P. Schultz Endowed Biomedical Research Award to JVB
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2723. doi:
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      Julia V Busik, Svetlana N Navitskaya, Harshini Chakravarthy, Chao Huang, Nermin Kady, Todd V Lydic, Walter V Esselman, Maria B Grant, Qi Wang; Targeting Acid Sphingomyelinase and Vascular Endothelial Growth Factor by miR-15a to Treat Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2723.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : The pathogenesis of diabetic retinopathy (DR) is known to involve pathways promoting the increase of pro-inflammatory cytokines, pro-inflammatory lipids and pro-angiogenic factors. These pathways are hypothesized to be regulated, as least in part, by microRNAs (miRNAs). We identified miR-15a as a key regulator of both pro-inflammatory and pro-angiogenic pathways. The purpose of this study was to determine the role of miR-15a in the pathogenesis of DR.

Methods : C56Bl6/J or Tie-2-miR15a-TG mice were made diabetic with STZ injections. Retinal vascular permeability was measured by FITC-albumin. Bone marrow derived gfp+ circulating angiogenic cells (CAC) with or without miR-15a mimic or antagomir transfection were intravireally injected their co-localization with retinal vasculature was observed by confocal microscopy. The human retinal pigment epithelial (HRPE) and human retinal endothelial cells (HREC) isolated from control and diabetic donors with or without miR-15a mimic or antagomir transfection were examined for ceramide levels by immunofluorescence and mass spectrometry. A luciferase assay was performed to detect miR-15a’s binding to ASM 3'-untranslated region (UTR).

Results : We demonstrated that miR-15a directly binds to ASM 3'-UTR in luciferase binding assay. miR-15a was reported to directly target VEGF-A. miR-15a expression was decreased in HREC isolated from diabetic donors (0.23±0.015 fold, p<0.001, n=6) and the retinas (0.27±0.021 fold, p<0.001, n=6) and bone marrow (0.031±0.023 fold, n=6) from type 1 STZ-induced diabetic mice compared with control mice. Correction of miR-15a expression using niR-15a mimic inhibited, while miR-15a antagomir further exacerbated ASM, VEGF-A and ceramide production in HRPE and HREC from control and diabetic models. miR-15a overexpression using antagomir improved CACs migration, homing to retinal vasculature and prevented retinal vascular damage in diabetic retina. Moreover, Tie-2-miR15a-TG mice were protected from diabetes-induced increase in retinal vascular permeability.

Conclusions : The results of this study demonstrate that dowregulation of miR-15a in diabetic retina contributes to diabetes-induced upregulation of ASM and VEGF-A and pathogenesis of diabetic retinopathy. Treatment strategies to increase miR-15a expression in diabetic retina could provide dual benefits by inhibiting both inflammatory and pro-angiogenic pathways.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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