PMID- 28931831 OWN - NLM STAT- MEDLINE DCOM- 20190701 LR - 20190701 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 7 IP - 1 DP - 2017 Sep 20 TI - Hyperhomocysteinemia Alters Retinal Endothelial Cells Barrier Function and Angiogenic Potential via Activation of Oxidative Stress. PG - 11952 LID - 10.1038/s41598-017-09731-y [doi] LID - 11952 AB - Hyperhomocysteinemia (HHcy) is associated with several human visual disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Breakdown of the blood-retinal barrier (BRB) is linked to vision loss in DR and AMD. Our previous work revealed that HHcy altered BRB in retinal endothelial cells in vivo. Here we hypothesize that homocysteine (Hcy) alters retinal endothelial cell barrier function and angiogenic potential via activation of oxidative stress. Human retinal endothelial cells (HRECs) treated with and without different concentrations of Hcy showed a reduction of tight junction protein expression, increased FITC dextran leakage, decreased transcellular electrical resistance and increased angiogenic potential. In addition, HRECs treated with Hcy showed increased production of reactive oxygen species (ROS). The anti-oxidant N-acetyl-cysteine (NAC) reduced ROS formation and decreased FITC-dextran leakage in Hcy treated HRECs. A mouse model of HHcy, in which cystathionine-beta-synthase is deficient (cbs (-/-)), was evaluated for oxidative stress by dichlolorofluorescein (DCF), dihydroethidium (DHE) staining. There was a marked increase in ROS production and augmented GSH reductase and antioxidant regulator NRF2 activity, but decreased antioxidant gene expression in retinas of hyperhomocysteinemic mice. Our results suggest activation of oxidative stress as a possible mechanism of HHcy induced retinal endothelial cell dysfunction. FAU - Mohamed, Riyaz AU - Mohamed R AD - Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, USA. FAU - Sharma, Isha AU - Sharma I AD - Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, USA. FAU - Ibrahim, Ahmed S AU - Ibrahim AS AD - Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, USA. AD - Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. FAU - Saleh, Heba AU - Saleh H AD - Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, USA. FAU - Elsherbiny, Nehal M AU - Elsherbiny NM AD - Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, USA. AD - Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. FAU - Fulzele, Sadanand AU - Fulzele S AD - Department: Orthopedic Surgery, MCG, Augusta University, Augusta, GA, USA. FAU - Elmasry, Khaled AU - Elmasry K AD - Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, USA. AD - Department of Cellular Biology and Anatomy, MCG, Augusta University, Augusta, GA, USA. FAU - Smith, Sylvia B AU - Smith SB AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, USA. AD - Department of Cellular Biology and Anatomy, MCG, Augusta University, Augusta, GA, USA. AD - Department of Ophthalmology, MCG, Augusta University, Augusta, GA, USA. FAU - Al-Shabrawey, Mohamed AU - Al-Shabrawey M AD - Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, USA. AD - Department of Cellular Biology and Anatomy, MCG, Augusta University, Augusta, GA, USA. AD - Department of Ophthalmology, MCG, Augusta University, Augusta, GA, USA. FAU - Tawfik, Amany AU - Tawfik A AD - Department of Oral Biology and Anatomy, Dental College of Georgia, Augusta University, Augusta, GA, USA. amtawfik@augusta.edu. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, USA. amtawfik@augusta.edu. AD - Department of Cellular Biology and Anatomy, MCG, Augusta University, Augusta, GA, USA. amtawfik@augusta.edu. AD - Department of Ophthalmology, MCG, Augusta University, Augusta, GA, USA. amtawfik@augusta.edu. LA - eng GR - R01 EY012830/EY/NEI NIH HHS/United States GR - R01 EY023315/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20170920 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 SB - IM MH - Animals MH - Cells, Cultured MH - Disease Models, Animal MH - Endothelial Cells/*pathology MH - Humans MH - Hyperhomocysteinemia/*complications/*pathology MH - Mice, Inbred C57BL MH - Neovascularization, Pathologic/*pathology MH - *Oxidative Stress MH - Permeability MH - Retina/*pathology MH - Retinal Diseases/*pathology PMC - PMC5607263 COIS- The authors declare that they have no competing interests. EDAT- 2017/09/22 06:00 MHDA- 2019/07/02 06:00 PMCR- 2017/09/20 CRDT- 2017/09/22 06:00 PHST- 2016/12/29 00:00 [received] PHST- 2017/07/28 00:00 [accepted] PHST- 2017/09/22 06:00 [entrez] PHST- 2017/09/22 06:00 [pubmed] PHST- 2019/07/02 06:00 [medline] PHST- 2017/09/20 00:00 [pmc-release] AID - 10.1038/s41598-017-09731-y [pii] AID - 9731 [pii] AID - 10.1038/s41598-017-09731-y [doi] PST - epublish SO - Sci Rep. 2017 Sep 20;7(1):11952. doi: 10.1038/s41598-017-09731-y.