Epigenetic modifications in hyperhomocysteinemia; potential role in diabetic retinopathy and age-related macular degeneration

Khaled Elmasry, Riyaz Mohamed, Isha Sharma, Nehal M. Elsherbiny, Yutao Liu, Mohamed Al-Shabrawey, Amany Mohamed Tawfik

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

To study Hyperhomocysteinemia (HHcy)-induced epigenetic modifications as potential mechanisms of blood retinal barrier (BRB) dysfunction, retinas isolated from three- week-old mice with elevated level of Homocysteine (Hcy) due to lack of the enzyme cystathionine β-synthase (cbs-/-, cbs+/- and cbs+/+), human retinal endothelial cells (HRECs), and human retinal pigmented epithelial cells (ARPE-19) treated with or without Hcy were evaluated for (1) histone deacetylases (HDAC), (2) DNA methylation (DNMT), and (3) miRNA analysis. Differentially expressed miRNAs in mice with HHcy were further compared with miRNA analysis of diabetic mice retinas (STZ) and miRNAs within the exosomes released from Hcy-treated RPEs. Differentially expressed miRNAs were further evaluated for predicted target genes and associated pathways using Ingenuity Pathway Analysis. HHcy significantly increased HDAC and DNMT activity in HRECs, ARPE-19, and cbs mice retinas, whereas inhibition of HDAC and DNMT decreased Hcy-induced BRB dysfunction. MiRNA profiling detected 127 miRNAs in cbs+/- and 39 miRNAs in cbs-/- mice retinas, which were significantly differentially expressed compared to cbs+/+. MiRNA pathway analysis showed their involvement in HDAC and DNMT activation, endoplasmic reticulum (ER), and oxidative stresses, inflammation, hypoxia, and angiogenesis pathways. Hcy-induced epigenetic modifications may be involved in retinopathies associated with HHcy, such as agerelated macular degeneration and diabetic retinopathy.

Original languageEnglish (US)
Pages (from-to)12562-12590
Number of pages29
JournalOncotarget
Volume9
Issue number16
DOIs
StatePublished - Jan 1 2018

Fingerprint

Hyperhomocysteinemia
Macular Degeneration
Diabetic Retinopathy
MicroRNAs
Epigenomics
Homocysteine
Histone Deacetylases
DNA Methylation
Retina
Blood-Retinal Barrier
Endothelial Cells
Cystathionine
Exosomes
Endoplasmic Reticulum Stress
Human Activities
Oxidative Stress
Epithelial Cells
Inflammation
Enzymes
Genes

Keywords

  • Age-related macular degeneration
  • Blood retinal barrier
  • Diabetic retinopathy
  • Epigenetic modifications
  • Hyperhomocysteinemia

ASJC Scopus subject areas

  • Oncology

Cite this

Epigenetic modifications in hyperhomocysteinemia; potential role in diabetic retinopathy and age-related macular degeneration. / Elmasry, Khaled; Mohamed, Riyaz; Sharma, Isha; Elsherbiny, Nehal M.; Liu, Yutao; Al-Shabrawey, Mohamed; Tawfik, Amany Mohamed.

In: Oncotarget, Vol. 9, No. 16, 01.01.2018, p. 12562-12590.

Research output: Contribution to journalArticle

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