Abstract
BackgroundThe ability to respond to changes in the extra-intracellular environment is prerequisite for cell survival. Cellular responses to the environment include elevating defense systems, such as the antioxidant defense system. Hypoxia-evoked reactive oxygen species (ROS)-driven oxidative stress is an underlying mechanism of retinal ganglion cell (RGC) death that leads to blinding disorders. The protein peroxiredoxin 6 (PRDX6) plays a pleiotropic role in negatively regulating death signaling in response to stressors, and thereby stabilizes cellular homeostasis.ResultsWe have shown that RGCs exposed to hypoxia (1%) or hypoxia mimetic cobalt chloride display reduced expression of PRDX6 with higher ROS expression and activation of NF-κB. These cells undergo apoptosis, while cells with over-expression of PRDX6 demonstrate resistance against hypoxia-driven RGC death. The RGCs exposed to hypoxia either with 1% oxygen or cobalt chloride (0-400 μM), revealed ~30%-70% apoptotic cell death after 48 and 72 h of exposure. Western analysis and real-time PCR showed elevated expression of PRDX6 during hypoxia at 24 h, while PRDX6 protein and mRNA expression declined from 48 h onwards following hypoxia exposure. Concomitant with this, RGCs showed increased ROS expression and activation of NF-κB with IkB phosphorylation/degradation, as examined with H2DCF-DA and transactivation assays. These hypoxia-induced adverse reactions could be reversed by over-expression of PRDX6.ConclusionBecause an abundance of PRDX6 in cells was able to attenuate hypoxia-induced RGC death, the protein could possibly be developed as a novel therapeutic agent acting to postpone RGC injury and delay the progression of glaucoma and other disorders caused by the increased-ROS-generated death signaling related to hypoxia.
Highlights
The ability to respond to changes in the extra-intracellular environment is prerequisite for cell survival
Hypoxia induced retinal ganglion cell (RGC) death with apoptosis, and these cells harbored elevated reactive oxygen species (ROS), reduced peroxiredoxin 6 (PRDX6), and increased NF-B expression Recently reports have documented that hypoxia-induced elevation in intracellular ROS is a cause of pathophysiology in cells and tissues [62]
We examined whether RGCs exposed to such stress showed reduced survival and died with apoptosis and displayed higher ROS levels
Summary
The ability to respond to changes in the extra-intracellular environment is prerequisite for cell survival. Hypoxia-evoked reactive oxygen species (ROS)-driven oxidative stress is an underlying mechanism of retinal ganglion cell (RGC) death that leads to blinding disorders. Uncontrolled rises in intracellular reactive oxygen species (ROS) are triggered by downregulation of expression and activity of protective molecules in response to changes in the extracellular environment. Such changes often include hypoxia, the scarcity of oxygen can lead to cell injury and death by apoptosis. Mammalian cells respond to fluctuations in their micro environmental oxygen by regulating defense genes such as stress response genes, heat shock factor, NF-B, and HIFa-1 These factors play occlusion or retinal vein thrombosis or atherosclerosis results in retinal hypoxia/ischemia. NF-B translocates to the nucleus and binds to DNA [10,34]
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