Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens

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• 作者：Lixin Wang^a ; ^{Lixin.Wang@AlconLabs.com} ; Julie A. Eldred^a ; ^{J.Eldred@uea.ac.uk} ; Peter Sidaway^b ; ^{p.sidaway@bham.ac.uk} ; Julie Sanderson^b ; ^{j.sanderon@uea.ac.uk} ; Andrew J.O. Smith^a ; ^{a.j.smith3@uae.ac.uk} ; Richard P. Bowater^a ; ^{R.Bowater@uae.ac.uk} ; John R. Reddan^c ; ^{reddan@oakland.edu} ; I. Michael Wormstone^a ; ^{i.m.wormstone@uea.ac.uk}
• 关键词：Sigma 1 receptor ; Oxidative stress ; ER stress ; Human ; Lens ; Cataract
• 刊名：Mechanisms of Ageing and Development
• 出版年：2012
• 出版时间：November-December, 2012
• 年：2012
• 卷：133
• 期：11-12
• 页码：665-674
• 全文大小：1631 K

文摘

Stimulation of sigma-1 receptors is reported to protect against oxidative stress. The present study uses cells and tissue from the human lens to elucidate the relationship between the sigma 1 receptor, ER stress and oxidative stress-induced damage. Exposure of the human lens cell line FHL124 to increasing concentrations of H₂O₂ led to reduced cell viability and increased apoptosis. In response to 30 ¦ÌM H₂O₂, levels of the ER stress proteins BiP, ATF6 and pEIF2¦Á were significantly increased within 4 h of exposure. Expression of the sigma 1 receptor was markedly increased in response to H₂O₂. Application of 10 and 30 ¦ÌM (+)-pentazocine, a sigma 1 receptor agonist, significantly inhibited the H₂O₂ induced cell death. (+)-Pentazocine also suppressed the oxidative stress induced reduction of pro-caspase 12 and suppressed the induction of the ER stress proteins BiP and EIF2¦Á. When applied to cultured human lenses, (+)-pentazocine protected against apoptotic cell death, LDH release and against H₂O₂ induced opacification. These data demonstrate that stimulation of the sigma 1 receptor provides significant protection from oxidative damage and is, therefore, a putative therapeutic approach to delay the onset of diseases that may be triggered by oxidative damage, including cataract formation.