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Xiangjun Yang, Jian Cai, Markus H Kuehn, Gulgun Tezel; Oxidative Stress is a “Molecular Risk Factor” in the Ocular Hypertensive Human Retina. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3673. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To better understand early molecular alterations determining the initiation of neurodegeneration in human glaucoma, we analyzed retinal proteomics alterations in the ocular hypertensive human retina.
Retina samples were obtained from two well-documented human donors with ocular hypertension (without glaucomatous injury) and two age- and gender-matched normotensive healthy controls. Retinal protein samples were analyzed by 2D-LC-MS/MS using oxygen isotope labeling for relative quantification of protein expression. Proteomics data were validated by Western blot analysis of selected proteins.
Out of 820 retinal proteins quantified, 59 exhibited over two-fold increased expression and 44 exhibited over two-fold decreased expression in sample 1, while the expression of 40 out of 763 proteins was increased and 54 was decreased in sample 2. Besides overall stress response characterized by up-regulated expression of various chaperones, stress-responsive heat shock proteins, and DNA repair enzymes, a number of antioxidants known to be involved in cellular redox homeostasis and superoxide radical degradation exhibited up-regulation in the ocular hypertensive human retina. The knowledge-based analysis by the Ingenuity Pathway Analysis indicated the nuclear factor-erythroid 2-related factor-2 (NRF2)-mediated oxidative stress response as a top canonical pathway significantly associated to our both datasets (the right-tailed Fisher’s exact test; p<0.0001). Over two-fold up-regulated retinal proteins in the ocular hypertensive human retina which were linked to oxidative stress response included superoxide dismutase 1 and 2, and thioredoxin. Despite the altered protein expression reflecting oxidative stress, no proteomics alterations, suggestive of ongoing cell death process or neuroinflammation, were detectable.
Ocular hypertension-related tissue stress in the human retina was evident by a prominent antioxidant response reflecting the oxidative stress and endogenous efforts to reduce oxidative stress-related damage. If antioxidant defense cannot overcome the oxidant generation then neurons become vulnerable to oxidative stress-related damage as evident in glaucoma. The up-regulated antioxidant response that we detected in the ocular hypertensive human retina may therefore indicate oxidative stress as a molecular risk factor for glaucoma development.
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