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The microRNA-7-mediated reduction in EPAC-1 contributes to vascular endothelial permeability and eNOS uncoupling in murine experimental retinopathy

Garcia-Morales, V., Friedrich, J., Jorna, L. M., Campos-Toimil, M., Hammes, H-P., Schmidt, M. & Krenning, G., Jun-2017, In : Acta diabetologica. 54, 6, p. 581-591 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

To investigate the consequences of oxidative stress and hypoxia on EPAC-1 expression during retinopathy.

Oxygen-induced retinopathy was induced in mice and EPAC-1 expression investigated by immunofluorescence. In silico analyses were used to identify a link between EPAC-1 expression and microRNA-7-5p in endothelial cells and confirmed by western blot analyses on cells expressing microRNA-7-5p. In vitro, endothelial cells were either incubated at 2% oxygen or transfected with microRNA-7-5p, and the effects of these treatments on EPAC-1 expression, endothelial hyperpermeability and NO production were assessed. In the Ins2Akita mouse model, levels of EPAC-1 expression as well as microRNA-7-5p were assessed by qPCR. Endothelial nitric oxide synthase was assessed by immunoblotting in the Ins2Akita model.

Hypoxia induces the expression of microRNA-7-5p that translationally inhibits the expression of EPAC-1 in endothelial cells, resulting in hyperpermeability and the loss of eNOS activity. Activation of EPAC-1 by the cAMP analogue 8-pCPT-2'-O-Me-cAMP reduced the sensitivity of EPAC-1 to oxidative stress and restored the endothelial permeability to baseline levels. Additionally, 8-pCPT-2'-O-Me-cAMP rescued eNOS activity and NO production. In mouse models of retinopathy, i.e., oxygen-induced retinopathy and the spontaneous diabetic heterozygous Ins2(Akita) mice, EPAC-1 levels are decreased which is associated with an increase in microRNA-7-5p expression and reduced eNOS activity.

In retinopathy, EPAC-1 expression is decreased in a microRNA-7-mediated manner, contributing to endothelial dysfunction. Pharmacological activation of remnant EPAC-1 rescues endothelial function. Collectively, these data indicate that EPAC-1 resembles an efficacious and druggable target molecule for the amelioration of (diabetic) retinopathy.

Original languageEnglish
Pages (from-to)581-591
Number of pages11
JournalActa diabetologica
Volume54
Issue number6
Publication statusPublished - Jun-2017

    Keywords

  • EPAC-1, Hypoxia, MicroRNA-7, Endothelial cell, Retinopathy, NUCLEOTIDE-EXCHANGE FACTOR, BARRIER FUNCTION, SMOOTH-MUSCLE, DOWN-REGULATION, VE-CADHERIN, CYCLIC-AMP, CAMP EPAC, HYPOXIA, CELLS, RELAXATION

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