PMID- 26885895 OWN - NLM STAT- MEDLINE DCOM- 20170109 LR - 20181113 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 7 IP - 8 DP - 2016 Feb 23 TI - Hyperhomocysteinemia disrupts retinal pigment epithelial structure and function with features of age-related macular degeneration. PG - 8532-45 LID - 10.18632/oncotarget.7384 [doi] AB - The disruption of retinal pigment epithelial (RPE) function and the degeneration of photoreceptors are cardinal features of age related macular degeneration (AMD); however there are still gaps in our understanding of underlying biological processes. Excess homocysteine (Hcy) has been reported to be elevated in plasma of patients with AMD. This study aimed to evaluate the direct effect of hyperhomocysteinemia (HHcy) on structure and function of RPE. Initial studies in a mouse model of HHcy, in which cystathionine-beta-synthase (cbs) was deficient, revealed abnormal RPE cell morphology with features similar to that of AMD upon optical coherence tomography (OCT), fluorescein angiography (FA), histological, and electron microscopic examinations. These features include atrophy, vacuolization, hypopigmentation, thickened basal laminar membrane, hyporeflective lucency, choroidal neovascularization (CNV), and disturbed RPE-photoreceptor relationship. Furthermore, intravitreal injection of Hcy per se in normal wild type (WT) mice resulted in diffuse hyper-fluorescence, albumin leakage, and CNV in the area of RPE. In vitro experiments on ARPE-19 showed that Hcy dose-dependently reduced tight junction protein expression, increased FITC dextran leakage, decreased transcellular electrical resistance, and impaired phagocytic activity. Collectively, our results demonstrated unreported effects of excess Hcy levels on RPE structure and function that lead to the development of AMD-like features. FAU - Ibrahim, Ahmed S AU - Ibrahim AS AD - Department of Oral Biology and Anatomy, College of Dental Medicine, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA. AD - Department of Biochemistry and Clinical Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. FAU - Mander, Suchreet AU - Mander S AD - Department of Oral Biology and Anatomy, College of Dental Medicine, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA. FAU - Hussein, Khaled A AU - Hussein KA AD - Department of Oral Biology and Anatomy, College of Dental Medicine, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA. AD - Oral and Dental Research Division, Department of Surgery and Medicine, National Research Center, Cairo, Egypt. FAU - Elsherbiny, Nehal M AU - Elsherbiny NM AD - Department of Oral Biology and Anatomy, College of Dental Medicine, Augusta University, Augusta, GA, USA. AD - Department of Biochemistry and Clinical Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. FAU - Smith, Sylvia B AU - Smith SB AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 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, College of Dental Medicine, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, 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, College of Dental Medicine, Augusta University, Augusta, GA, USA. AD - James and Jean Culver Vision Discovery Institute, Medical College of Georgia (MCG), Augusta University, Augusta, GA, USA. AD - Department of Cellular Biology and Anatomy, MCG, Augusta University, Augusta, GA, USA. LA - eng GR - R01 EY012830/EY/NEI NIH HHS/United States GR - R01 EY023315/EY/NEI NIH HHS/United States GR - 5R01EY023315-02/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - EC 4.2.1.22 (Cystathionine beta-Synthase) SB - IM MH - Animals MH - Blotting, Western MH - Cells, Cultured MH - Choroidal Neovascularization/metabolism/*pathology MH - Cystathionine beta-Synthase/*physiology MH - Female MH - Fluorescein Angiography MH - Fluorescent Antibody Technique MH - Humans MH - Hyperhomocysteinemia/*physiopathology MH - Immunoenzyme Techniques MH - Macular Degeneration/metabolism/*pathology MH - Male MH - Mice MH - Mice, Knockout MH - Retinal Pigment Epithelium/metabolism/*pathology MH - Tomography, Optical Coherence PMC - PMC4890985 OTO - NOTNLM OT - Gerotarget OT - age related macular degeneration OT - cystathionine-beta-synthase and mouse OT - hyperhomocysteinemia OT - retinal pigment epithelium COIS- CONFLICTS OF INTEREST There is no conflict of interest. EDAT- 2016/02/18 06:00 MHDA- 2017/01/10 06:00 PMCR- 2016/02/23 CRDT- 2016/02/18 06:00 PHST- 2015/12/23 00:00 [received] PHST- 2016/01/30 00:00 [accepted] PHST- 2016/02/18 06:00 [entrez] PHST- 2016/02/18 06:00 [pubmed] PHST- 2017/01/10 06:00 [medline] PHST- 2016/02/23 00:00 [pmc-release] AID - 7384 [pii] AID - 10.18632/oncotarget.7384 [doi] PST - ppublish SO - Oncotarget. 2016 Feb 23;7(8):8532-45. doi: 10.18632/oncotarget.7384.