TY - JOUR
T1 - Epigenetic modifications in hyperhomocysteinemia; potential role in diabetic retinopathy and age-related macular degeneration
AU - Elmasry, Khaled
AU - Mohamed, Riyaz
AU - Sharma, Isha
AU - Elsherbiny, Nehal M.
AU - Liu, Yutao
AU - Al-Shabrawey, Mohamed
AU - Tawfik, Amany
N1 - Funding Information:
This study was supported by startup fund from the Dental College of Georgia, a pilot project grant from the James & Jean Culver Vision Discovery Institute (VDI) and American Heart Association (AHA) Scientist Development Grant award #16SDG3070001 and 5R01EY023315-02 grant. We would like to thank the Augusta University undergraduate student Sung Chu for his help in the analytical part and Georgia Cancer Center, Integrated Genomics Core, especially Dr. Eiko Kitamura, PhD, for their great help in performing our microarray studies
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Age-related macular degeneration
KW - Blood retinal barrier
KW - Diabetic retinopathy
KW - Epigenetic modifications
KW - Hyperhomocysteinemia
UR - http://www.scopus.com/inward/record.url?scp=85042561298&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042561298&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.24333
DO - 10.18632/oncotarget.24333
M3 - Article
C2 - 29560091
AN - SCOPUS:85042561298
SN - 1949-2553
VL - 9
SP - 12562
EP - 12590
JO - Oncotarget
JF - Oncotarget
IS - 16
ER -
