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

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

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Article number8412
Pages1-18
Number of pages18
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 1 Dec 2017

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Fibrinolysin
Glaucoma
Retina
Methionine
Serpins
Serine Proteinase Inhibitors
Extracellular Matrix Proteins
neuroserpin
Superoxide Dismutase
Extracellular Matrix
Catalytic Domain
Oxidative Stress

Bibliographical note

Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Cite this

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title = "Glaucoma is associated with plasmin proteolytic activation mediated through oxidative inactivation of neuroserpin",
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.",
author = "Vivek Gupta and Mehdi Mirzaei and Gupta, {Veer Bala} and Nitin Chitranshi and Yogita Dheer and {Vander Wall}, Roshana and Mojdeh Abbasi and Yuyi You and Roger Chung and Stuart Graham",
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year = "2017",
month = "12",
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Glaucoma is associated with plasmin proteolytic activation mediated through oxidative inactivation of neuroserpin. / Gupta, Vivek; Mirzaei, Mehdi; Gupta, Veer Bala; Chitranshi, Nitin; Dheer, Yogita; Vander Wall, Roshana; Abbasi, Mojdeh; You, Yuyi; Chung, Roger; Graham, Stuart.

In: Scientific Reports, Vol. 7, 8412, 01.12.2017, p. 1-18.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Gupta, Vivek

AU - Mirzaei, Mehdi

AU - Gupta, Veer Bala

AU - Chitranshi, Nitin

AU - Dheer, Yogita

AU - Vander Wall, Roshana

AU - Abbasi, Mojdeh

AU - You, Yuyi

AU - Chung, Roger

AU - Graham, Stuart

N1 - Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

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