Glaucoma is associated with plasmin proteolytic activation mediated through oxidative inactivation of neuroserpin

Vivek Gupta,Mojdeh Abbasi,Stuart Graham,Veer Bala Gupta,Roger Chung,Roshana Vander Wall,Yogita Dheer,Yuyi You,Nitin Chitranshi,Mehdi Mirzaei

doi:10.1038/s41598-017-08688-2

Vivek Gupta, Mojdeh Abbasi + Show 8 more

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https://doi.org/10.1038/s41598-017-08688-2

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Abstract

Neuroserpin is a serine protease inhibitor that regulates the activity of plasmin and its activators in the neuronal tissues. This study provides novel evidence of regulatory effect of the neuroserpin on plasmin proteolytic activity in the retina in glaucoma. Human retinal and vitreous tissues from control and glaucoma subjects as well as retinas from experimental glaucoma rats were analysed to establish changes in plasmin and neuroserpin activity. Neuroserpin undergoes oxidative inactivation in glaucoma which leads to augmentation of plasmin activity. Neuroserpin contains several methionine residues in addition to a conserved reactive site methionine and our study revealed enhanced oxidation of Met residues in the serpin under glaucoma conditions. Met oxidation was associated with loss of neuroserpin inhibitory activity and similar findings were observed in the retinas of superoxide dismutase (SOD) mutant mice that have increased oxidative stress. Treatment of purified neuroserpin with H2O2 further established that Met oxidation inversely correlated with its plasmin inhibitory activity. Dysregulation of the plasmin proteolytic system associated with increased degradation of the extracellular matrix (ECM) proteins in the retina. Collectively, these findings delineate a novel molecular basis of plasmin activation in glaucoma and potentially for other neuronal disorders with implications in disease associated ECM remodelling.

Highlights

Glaucoma is the most common cause of irreversible vision loss marked by retinal ganglion cell (RGC) degeneration and excavation of the optic nerve head
To investigate whether neuroserpin levels exhibit any alterations under glaucoma conditions, retinal, optic nerve head (ONH) and vitreous tissue lysates from human control and glaucoma samples were subjected to immunoblotting analysis using actin as a loading control
Our results indicated that the retinal and vitreous tissues of human glaucoma subjects and retinas of animal model of chronically increased intraocular pressure (IOP) demonstrated enhanced plasmin amidolytic activity and reduced neuroserpin protease inhibitory activity

Summary

Introduction

Glaucoma is the most common cause of irreversible vision loss marked by retinal ganglion cell (RGC) degeneration and excavation of the optic nerve head. Increased intraocular pressure (IOP) is a prominent manifestation of glaucoma and controlling IOP remains the primary means of disease management Several factors such as pressure induced remodelling of the lamina cribrosa, axonal compression of the RGCs, obstruction in the retrograde flow of neurotrophins to RGCs, impediments in axonal transport along the optic nerve, chronic ischemic insult and digestion of the extracellular matrix (ECM) by proteolytic activity have been suggested to play a role in the glaucoma pathology[1,2,3]. Metastatic lung and breast cancer cells in brain depict increased neuroserpin expression and this is shown to suppress the negative effects of plasmin activation[17]. The focus of the study was primarily to advance knowledge of the mechanism underlying glaucoma pathogenesis but may have relevance to other health and neurodegenerative conditions linked with oxidative stress and imbalance of plasmin-neuroserpin equilibrium

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