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Oxidative Stress and TGF-β2 Increase Heat Shock Protein 27 Expression in Human Optic Nerve Head Astrocytes

¹From the Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany; ²Department of Anatomy, University of Regensburg, Regensburg, Germany; ³Departments of Anatomy and ⁵Ophthalmology, Friedrich-Alexander-University, Erlangen, Germany; and ⁴Department of Biomolecular Chemistry NCMLS, Radboud University Njimegen, Njimegen, The Netherlands.

PURPOSE. Reactive astrocytes of glaucomatous optic nerve heads (ONHs) are characterized by an increased expression of transforming growth factor (TGF)-β2 and heat shock proteins (Hsps) such as Hsp27. The goal of the present study was to determine the effect of oxidative stress on TGF-β2 and Hsp27 expression in human ONH astrocytes.

METHODS. Cultured ONH astrocytes were exposed to 100, 200, and 400 µM hydrogen peroxide (H₂O₂) for 1 hour. Levels of TGF-β2 were analyzed by ELISA. Additionally, cells were treated with 1.0 ng/mL TGF-β2 for 12, 24, and 48 hours, respectively. Expression of Hsp27 was detected by immunohistochemistry, real-time PCR, and Western blot analyses. To investigate the role of signal transduction proteins, cells were pretreated with the specific inhibitors SB203580, PD98059, U0126, and SP600125. Furthermore, induction of p38MAP kinase and its phosphorylated form were determined by Western blot analyses.

RESULTS. H₂O₂ exposure increased the secretion of TGF-β2. Both H₂O₂ and TGF-β2 increased the Hsp27 expression. Pretreatment of cells with SB203580, an inhibitor for p38MAP kinase, reduced the H₂O₂- and TGF-β2-stimulated Hsp27 expression, whereas pretreatment with PD98059 and U0126, specific inhibitors of ERK1/2, and SP600125, a specific c-Jun N-terminal kinase inhibitor, had no effects. H₂O₂ and TGF-β2 upregulated the phosphorylated p38MAP kinase.

CONCLUSIONS. Oxidative stress increased TGF-β2 secretion in cultured human ONH astrocytes. Both H₂O₂ and TGF-β2 increased Hsp27 expression via p38MAP kinase activation. Therefore, it is tempting to speculate that reduction of oxidative stress and TGF-β2 may help to minimize the incidence of characteristic changes in the ONH of patients with glaucoma.