title: Dual Anti-Inflammatory and Anti-Angiogenic Action of miR-15a in Diabetic Retinopathy.
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.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Navitskaya
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Harshini
authors.initials: H
authors.lastname: Chakravarthy
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Chao
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Nermin
authors.initials: N
authors.lastname: Kady
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Lydic
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States.
authors.forename: Ke-Jie
authors.initials: KJ
authors.lastname: Yin
authors.affiliation: The Medical College of Georgia, at Augusta University, Augusta, GA 30912, United States.
authors.forename: Folami Lamoke
authors.initials: FL
authors.lastname: Powell
authors.affiliation: The Medical College of Georgia, at Augusta University, Augusta, GA 30912, United States.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Martin
authors.affiliation: Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, United States. Electronic address: busik@msu.edu.
authors.forename: Julia V
authors.initials: JV
authors.lastname: Busik
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002518:Ceramides / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D042783:Endothelial Cells; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D034622:RNA Interference; D051381:Rats; D012160:Retina / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism; D012171:Retinal Vessels; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D002518:Ceramides; D035683:MicroRNAs; C544301:Mirn15a microRNA, mouse; D042461:Vascular Endothelial Growth Factor A; D013108:Sphingomyelin Phosphodiesterase
keywords: Diabetic retinopathy; Dyslipidemias; Sphingolipids; Vascular system injuries; microRNA