Research Papers: Gerotarget (Focus on Aging):

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 and Amany Tawfik _

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Oncotarget. 2018; 9:12562-12590. https://doi.org/10.18632/oncotarget.24333

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Khaled Elmasry1,2,3,4, Riyaz Mohamed1,3, Isha Sharma1,3, Nehal M. Elsherbiny5, Yutao Liu2,3, Mohamed Al-Shabrawey1,2,3,4 and Amany Tawfik1,2,3

1Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA

2Department of Cellular Biology and Anatomy, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA

3James and Jean Culver Vision Discovery Institute, MCG, Augusta University, August, GA, USA

4Department of Human Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

5Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt

Correspondence to:

Amany Tawfik, email: [email protected]

Keywords: epigenetic modifications; blood retinal barrier; diabetic retinopathy; age-related macular degeneration; hyperhomocysteinemia; Gerotarget

Received: August 06, 2017     Accepted: January 24, 2018     Published: January 29, 2018


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 age-related macular degeneration and diabetic retinopathy.

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