Dataset Information

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.

SUBMITTER: Wang Q

PROVIDER: S-EPMC5049929 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Wang Qi Q Navitskaya Svetlana S Chakravarthy Harshini H Huang Chao C Kady Nermin N Lydic Todd A TA Chen Y Eugene YE Yin Ke-Jie KJ Powell Folami Lamoke FL Martin Pamela M PM Grant Maria B MB Busik Julia V JV

EBioMedicine 20160808

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 inhib ...[more]

PMID: 27531575

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Project description:BackgroundGenetic factors are implicated in the progression of DR-a global cause of blindness. Hence, the current work investigated the association of HIF-1α rs11549465 and VEGF rs3025039 genetic variants with the different stages of retinopathy among T2DM Egyptian patients. The crosslinks of these variants were explored with angiogenesis (VEGF), inflammation (AGEP and VCAM-1), and anti-inflammation (CTRP3) markers. Two hundred eighty-eight subjects were recruited in this study: 72 served as controls and 216 were having T2DM and were divided into diabetics without retinopathy (DWR), diabetics with non-proliferative retinopathy (NPDR), and diabetics with proliferative retinopathy (PDR). The genetic variants were analyzed using PCR-RFLP and their associations with NPDR and PDR were statistically tested. The circulating levels of AGEP, VCAM-1, HIF-1α, VEGF, and CTRP3 were assayed followed by analyzing their associations statistically with the studied variants.ResultsOnly HIF-1α rs11549465 genetic variant (recessive model) was significantly associated with the development of NPDR among T2DM patients (p < 0.025) with a significant correlation with the circulating HIF-1α level (p < 0.0001). However, this variant was not associated with PDR progression. Neither HIF-1α rs11549465 nor VEGF rs3025039 genetic variants were associated with the PDR progression. The circulating AGEP, VCAM-1, HIF-1α, and VEGF were significantly elevated (p < 0.0001) while the CTRP3 was significantly decreased (p < 0.0001) in NPDR and PDR groups. The HIF-1α rs11549465 CT and/or TT genotype carriers were significantly associated with AGEP and VCAM-1 levels in the NPDR group, while it showed a significant association with the CTRP3 level in the PDR group. The VEGF rs3025039 TT genotype carriers showed only a significant association with the CTRP3 level in the PDR group.ConclusionThe significant association of HIF-1α rs11549465 other than VEGF rs3025039 with the initiation of NPDR in T2DM Egyptian patients might protect them from progression to the proliferative stage via elevating circulating HIF-1α. However, this protective role was not enough to prevent the development of NPDR because of enhancing angiogenesis and inflammation together with suppressing anti-inflammation. The non-significant association of HIF-1α rs11549465 with PDR among T2DM patients could not make this variant a risk factor for PDR progression.

Dataset Information

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

Publications

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

Similar Datasets

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