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Abstract #74367 Published in IGR 19-1
Prdx6 retards senescence and restores trabecular meshwork cell health by regulating reactive oxygen species
Chhunchha B; Singh P; Stamer WD; Singh DPCell death discovery 2017; 3: 17060
A progressive decline in antioxidant potential and accumulation of reactive oxygen species (ROS) are major causes of pathogenesis of several diseases, including glaucoma. Trabecular meshwork (TM) dysfunction resulting in higher intraocular pressure (IOP) is a hallmark of glaucoma, but its causes are unclear. Using human (h) TM cells derived from glaucomatous and normal subjects of different ages and cells facing oxidative-stress, we showed that specific loss of moonlighting antioxidant protein Peroxiredoxin (Prdx) 6 in aging or in glaucomatous TM cells caused ROS accumulation and pathobiological changes in TM cells. Prdx6 limits the levels of ROS, thus preventing overstimulation of genes and resultant deleterious effects. We found that Prdx6 levels declined in aging and were reduced dramatically in glaucomatous and aged TM cells. Biochemical assays revealed enhanced levels of ROS, and high expression/activation of TGFβs and its responsive extracellular matrix genes α-SM, fibronectin, TGase2 and Tsp1 in aged or glaucomatous cells. Furthermore, hTM cells displayed typical features of the combined effects of TGFβs and oxidative-stress-induced cellular changes, showing increased levels of lipid peroxidation, oxidative DNA damage, and senescence markers p16, p21 and SA-βgal activity, along with reduced levels of telomerase expression and activity. Exposure to oxidative-stress (H2O2) or knocking down of Prdx6 (with antisense) accelerated this process. Importantly, Prdx6 delivery to sick or aged TM cells reversed the process. We propose Prdx6 as a potential therapeutic target to guard the TM from oxidative-stress and age-dependent accumulation of ROS by balancing redox-homeostasis to prevent ocular disorders, like glaucoma.
Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha,NE, USA.
Full articleClassification:
2.5.1 Trabecular meshwork (Part of: 2 Anatomical structures in glaucoma > 2.5 Meshwork)
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
3.7 Biochemistry (Part of: 3 Laboratory methods)
3.9 Pathophysiology (Part of: 3 Laboratory methods)
