Proteomics Reveals the Potential Protective Mechanism of Hydrogen Sulfide on Retinal Ganglion Cells in an Ischemia/Reperfusion Injury Animal Model

Abstract

Glaucoma is the leading cause of irreversible blindness and is characterized by progressive retinal ganglion cell (RGC) degeneration. Hydrogen sulfide (H2S) is a potent neurotransmitter and has been proven to protect RGCs against glaucomatous injury in vitro and in vivo. This study is to provide an overall insight of H2S’s role in glaucoma pathophysiology. Ischemia-reperfusion injury (I/R) was induced in Sprague-Dawley rats (n = 12) by elevating intraocular pressure to 55 mmHg for 60 min. Six of the animals received intravitreal injection of H2S precursor prior to the procedure and the retina was harvested 24 h later. Contralateral eyes were assigned as control. RGCs were quantified and compared within the groups. Retinal proteins were analyzed via label-free mass spectrometry based quantitative proteomics approach. The pathways of the differentially expressed proteins were identified by ingenuity pathway analysis (IPA). H2S significantly improved RGC survival against I/R in vivo (p < 0.001). In total 1115 proteins were identified, 18 key proteins were significantly differentially expressed due to I/R and restored by H2S. Another 11 proteins were differentially expressed following H2S. IPA revealed a significant H2S-mediated activation of pathways related to mitochondrial function, iron homeostasis and vasodilation. This study provides first evidence of the complex role that H2S plays in protecting RGC against I/R.

Hydrogen Sulfide: Novel Endogenous and Exogenous Modulator of Oxidative Stress in Retinal Degeneration Diseases

“…In our previous studies, we have also revealed that exogenous H 2 S activates the pathways related to OS, such as iron regulation, ROS clearance, and mitochondrial homeostasis and function [ 135 ]. Vitamin C also plays an important role as an antioxidant in the retina and brain [ 136 ].…”

Current Perspective of Hydrogen Sulfide as a Novel Gaseous Modulator of Oxidative Stress in Glaucoma

“…Excess iron promotes the generation of damaging hydroxyl groups from oxidation reaction products, thus exacerbating oxidative stress [ 74 , 75 ]. Current studies have found that iron metabolism is critical for neurotransmitter production and myelin synthesis [ 76 ]. In a number of studies on neurodegenerative diseases, it has been found that increased levels of iron in the brains of animals and human produce significant cognitive impairment [ 77 , 78 , 79 , 80 ].…”

“…Maintaining heme release can effectively maintain iron homeostasis and control redox reactions. Under both hyperoxia conditions and ischemia-reperfusion injury, H 2 S has been shown to modulate the heme release, by interacting with heme oxygenase and biliverdin reductase A, respectively, while increasing the capacity of antioxidant production [ 76 , 86 , 87 ].…”

“…Glutaredoxin-3 (Glrx3) is an important factor in the assembly of Fe-S clusters [ 96 ]. H 2 S is shown to regulate intracellular Glrx3 levels, thereby maintaining iron homeostasis and regulating the redox state in cells [ 76 ].…”

“…In research of altered protein expression in the retina in a mouse model of acute IOP H 2 S was found to limit ROS production by inhibiting mitochondrial oxygen consumption and leading to increased intracellular oxygen tension, possibly through upregulating HIF1-α levels and decreasing mitochondrial oxidative phosphorylation levels [ 76 ]. This research also found that H 2 S promotes the production of ketone bodies, which can replace glucose as an energy source and enhance retinal resistance to oxidative stress, thereby reducing neuronal damage [ 76 ].…”