Hyperhomocysteinemia Alters Retinal Endothelial Cells Barrier Function and Angiogenic Potential Via Activation of Oxidative Stress

Overview

Journal Sci Rep

Specialty Science

Date 2017 Sep 22

PMID 28931831

Citations 25

Authors

Riyaz Mohamed

Isha Sharma

Ahmed S Ibrahim

Heba Saleh

Nehal M Elsherbiny

Sadanand Fulzele

Khaled Elmasry

Sylvia B Smith

Mohamed Al-Shabrawey

Amany Tawfik

Affiliations

Soon will be listed here.

Abstract

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-β-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.

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References

Wotherspoon F, Laight D, Browne D, Turner C, Meeking D, Allard S . Plasma homocysteine, oxidative stress and endothelial function in patients with Type 1 diabetes mellitus and microalbuminuria. Diabet Med. 2006; 23(12):1350-6. DOI: 10.1111/j.1464-5491.2006.01980.x. View

Montoya L, Pluth M . Selective turn-on fluorescent probes for imaging hydrogen sulfide in living cells. Chem Commun (Camb). 2012; 48(39):4767-9. PMC: 3340910. DOI: 10.1039/c2cc30730h. View

Beard Jr R, Reynolds J, Bearden S . Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions. Blood. 2011; 118(7):2007-14. PMC: 3158726. DOI: 10.1182/blood-2011-02-338269. View

Ibrahim A, Mander S, Hussein K, Elsherbiny N, Smith S, Al-Shabrawey M . Hyperhomocysteinemia disrupts retinal pigment epithelial structure and function with features of age-related macular degeneration. Oncotarget. 2016; 7(8):8532-45. PMC: 4890985. DOI: 10.18632/oncotarget.7384. View

Galasso G, Schiekofer S, Sato K, Shibata R, Handy D, Ouchi N . Impaired angiogenesis in glutathione peroxidase-1-deficient mice is associated with endothelial progenitor cell dysfunction. Circ Res. 2005; 98(2):254-61. PMC: 1472658. DOI: 10.1161/01.RES.0000200740.57764.52. View

Cunha-Vaz J, Bernardes R, Lobo C . Blood-retinal barrier. Eur J Ophthalmol. 2012; 21 Suppl 6:S3-9. DOI: 10.5301/EJO.2010.6049. View

Ibrahim A, Tawfik A, Hussein K, Elshafey S, Markand S, Rizk N . Pigment epithelium-derived factor inhibits retinal microvascular dysfunction induced by 12/15-lipoxygenase-derived eicosanoids. Biochim Biophys Acta. 2015; 1851(3):290-8. PMC: 4312733. DOI: 10.1016/j.bbalip.2014.12.017. View

Scholl S, Augustin A, Loewenstein A, Rizzo S, Kupperman B . General pathophysiology of macular edema. Eur J Ophthalmol. 2012; 21 Suppl 6:S10-9. DOI: 10.5301/EJO.2010.6050. View

Gunasekar P, Kanthasamy A, Borowitz J, Isom G . NMDA receptor activation produces concurrent generation of nitric oxide and reactive oxygen species: implication for cell death. J Neurochem. 1995; 65(5):2016-21. DOI: 10.1046/j.1471-4159.1995.65052016.x. View

10.

Kanani P, Sinkey C, BROWNING R, Allaman M, Knapp H, HAYNES W . Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation. 1999; 100(11):1161-8. DOI: 10.1161/01.cir.100.11.1161. View

11.

Ergul A, Johansen J, Stromhaug C, Harris A, Hutchinson J, Tawfik A . Vascular dysfunction of venous bypass conduits is mediated by reactive oxygen species in diabetes: role of endothelin-1. J Pharmacol Exp Ther. 2004; 313(1):70-7. DOI: 10.1124/jpet.104.078105. View

12.

Faraci F, Lentz S . Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke. 2004; 35(2):345-7. DOI: 10.1161/01.STR.0000115161.10646.67. View

13.

Kowluru R, Tang J, Kern T . Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes. 2001; 50(8):1938-42. DOI: 10.2337/diabetes.50.8.1938. View

14.

Tyagi N, Sedoris K, Steed M, Ovechkin A, Moshal K, Tyagi S . Mechanisms of homocysteine-induced oxidative stress. Am J Physiol Heart Circ Physiol. 2005; 289(6):H2649-56. DOI: 10.1152/ajpheart.00548.2005. View

15.

Zhang B, Qiu L, Fu M, Hu S . Interference in mevalonate pathway ameliorates homocysteine-induced endothelium-dysfunction. Eur J Pharmacol. 2012; 692(1-3):61-8. DOI: 10.1016/j.ejphar.2012.07.014. View

16.

Lai W, Kan M . Homocysteine-Induced Endothelial Dysfunction. Ann Nutr Metab. 2015; 67(1):1-12. DOI: 10.1159/000437098. View

17.

Erickson K, Sundstrom J, Antonetti D . Vascular permeability in ocular disease and the role of tight junctions. Angiogenesis. 2007; 10(2):103-17. DOI: 10.1007/s10456-007-9067-z. View

18.

Deissler H, Deissler H, Lang G . Inhibition of protein kinase C is not sufficient to prevent or reverse effects of VEGF165 on claudin-1 and permeability in microvascular retinal endothelial cells. Invest Ophthalmol Vis Sci. 2009; 51(1):535-42. DOI: 10.1167/iovs.09-3917. View

19.

Antonetti D, Barber A, Bronson S, Freeman W, Gardner T, Jefferson L . Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes. 2006; 55(9):2401-11. DOI: 10.2337/db05-1635. View

20.

Bharadwaj A, Appukuttan B, Wilmarth P, Pan Y, Stempel A, Chipps T . Role of the retinal vascular endothelial cell in ocular disease. Prog Retin Eye Res. 2012; 32:102-80. PMC: 3679193. DOI: 10.1016/j.preteyeres.2012.08.004. View