Hydrogen sulfide stimulates xanthine oxidoreductase conversion to nitrite reductase and formation of NO
Cardiovascular disease is the leading cause of death and disability worldwide with increased oxidative stress and reduced NO bioavailability serving as key risk factors. For decades, elevation in protein abundance and enzymatic activity of xanthine oxidoreductase (XOR) under hypoxic/inflammatory con...
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doaj-d18ee3c620724710a536a1646f1261592020-11-25T03:16:17ZengElsevierRedox Biology2213-23172020-07-0134101447Hydrogen sulfide stimulates xanthine oxidoreductase conversion to nitrite reductase and formation of NOSibile Pardue0Gopi K. Kolluru1Xinggui Shen2Sara E. Lewis3Courtney B. Saffle4Eric E. Kelley5Christopher G. Kevil6Department of Pathology, LSU Health Sciences Center, Shreveport, LA, USADepartment of Pathology, LSU Health Sciences Center, Shreveport, LA, USADepartment of Pathology, LSU Health Sciences Center, Shreveport, LA, USADepartment of Physiology and Pharmacology, West Virginia University, United StatesDepartment of Physiology and Pharmacology, West Virginia University, United StatesDepartment of Physiology and Pharmacology, West Virginia University, United StatesDepartment of Pathology, LSU Health Sciences Center, Shreveport, LA, USA; Department of Cellular Biology and Anatomy, LSU Health Sciences Center, Shreveport, LA, USA; Department of Molecular and Cellular Physiology, LSU Health Sciences Center, Shreveport, LA, USA; Corresponding author. Department of Pathology LSU Health Sciences Center, Shreveport, LA, 71130, United States.Cardiovascular disease is the leading cause of death and disability worldwide with increased oxidative stress and reduced NO bioavailability serving as key risk factors. For decades, elevation in protein abundance and enzymatic activity of xanthine oxidoreductase (XOR) under hypoxic/inflammatory conditions has been associated with organ damage and vascular dysfunction. Recent reports have challenged this dogma by identifying a beneficial function for XOR, under similar hypoxic/acidic conditions, whereby XOR catalyzes the reduction of nitrite (NO2-) to nitric oxide (NO) through poorly defined mechanisms. We previously reported that hydrogen sulfide (H2S/sulfide) confers significant vascular benefit under these same conditions via NO2- mediated mechanisms independent of nitric oxide synthase (NOS). Here we report for the first time the convergence of H2S, XOR, and nitrite to form a concerted triad for NO generation. Specifically, hypoxic endothelial cells show a dose-dependent, sulfide and polysulfide (diallyl trisulfide (DATS)-induced, NOS-independent NO2- reduction to NO that is dependent upon the enzymatic activity of XOR. Interestingly, nitrite reduction to NO was found to be slower and more sustained with DATS compared to H2S. Capacity for sulfide/polysulfide to produce an XOR-dependent impact on NO generation translates to salutary actions in vivo as DATS administration in cystathionine-γ-lyase (CSE) knockout mice significantly improved hindlimb ischemia blood flow post ligation, while the XOR-specific inhibitor, febuxostat (Febx), abrogated this benefit. Moreover, flow-mediated vasodilation (FMD) in CSE knockout mice following administration of DATS resulted in greater than 4-fold enhancement in femoral artery dilation while co-treatment with Febx completely completely abrogated this effect. Together, these results identify XOR as a focal point of convergence between sulfide- and nitrite-mediated signaling, as well as affirm the critical need to reexamine current dogma regarding inhibition of XOR in the context of vascular dysfunction.http://www.sciencedirect.com/science/article/pii/S2213231719315885SulfideNitric oxideXanthine oxidaseNitritePolysulfideHydrogen sulfide |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sibile Pardue Gopi K. Kolluru Xinggui Shen Sara E. Lewis Courtney B. Saffle Eric E. Kelley Christopher G. Kevil |
spellingShingle |
Sibile Pardue Gopi K. Kolluru Xinggui Shen Sara E. Lewis Courtney B. Saffle Eric E. Kelley Christopher G. Kevil Hydrogen sulfide stimulates xanthine oxidoreductase conversion to nitrite reductase and formation of NO Redox Biology Sulfide Nitric oxide Xanthine oxidase Nitrite Polysulfide Hydrogen sulfide |
author_facet |
Sibile Pardue Gopi K. Kolluru Xinggui Shen Sara E. Lewis Courtney B. Saffle Eric E. Kelley Christopher G. Kevil |
author_sort |
Sibile Pardue |
title |
Hydrogen sulfide stimulates xanthine oxidoreductase conversion to nitrite reductase and formation of NO |
title_short |
Hydrogen sulfide stimulates xanthine oxidoreductase conversion to nitrite reductase and formation of NO |
title_full |
Hydrogen sulfide stimulates xanthine oxidoreductase conversion to nitrite reductase and formation of NO |
title_fullStr |
Hydrogen sulfide stimulates xanthine oxidoreductase conversion to nitrite reductase and formation of NO |
title_full_unstemmed |
Hydrogen sulfide stimulates xanthine oxidoreductase conversion to nitrite reductase and formation of NO |
title_sort |
hydrogen sulfide stimulates xanthine oxidoreductase conversion to nitrite reductase and formation of no |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2020-07-01 |
description |
Cardiovascular disease is the leading cause of death and disability worldwide with increased oxidative stress and reduced NO bioavailability serving as key risk factors. For decades, elevation in protein abundance and enzymatic activity of xanthine oxidoreductase (XOR) under hypoxic/inflammatory conditions has been associated with organ damage and vascular dysfunction. Recent reports have challenged this dogma by identifying a beneficial function for XOR, under similar hypoxic/acidic conditions, whereby XOR catalyzes the reduction of nitrite (NO2-) to nitric oxide (NO) through poorly defined mechanisms. We previously reported that hydrogen sulfide (H2S/sulfide) confers significant vascular benefit under these same conditions via NO2- mediated mechanisms independent of nitric oxide synthase (NOS). Here we report for the first time the convergence of H2S, XOR, and nitrite to form a concerted triad for NO generation. Specifically, hypoxic endothelial cells show a dose-dependent, sulfide and polysulfide (diallyl trisulfide (DATS)-induced, NOS-independent NO2- reduction to NO that is dependent upon the enzymatic activity of XOR. Interestingly, nitrite reduction to NO was found to be slower and more sustained with DATS compared to H2S. Capacity for sulfide/polysulfide to produce an XOR-dependent impact on NO generation translates to salutary actions in vivo as DATS administration in cystathionine-γ-lyase (CSE) knockout mice significantly improved hindlimb ischemia blood flow post ligation, while the XOR-specific inhibitor, febuxostat (Febx), abrogated this benefit. Moreover, flow-mediated vasodilation (FMD) in CSE knockout mice following administration of DATS resulted in greater than 4-fold enhancement in femoral artery dilation while co-treatment with Febx completely completely abrogated this effect. Together, these results identify XOR as a focal point of convergence between sulfide- and nitrite-mediated signaling, as well as affirm the critical need to reexamine current dogma regarding inhibition of XOR in the context of vascular dysfunction. |
topic |
Sulfide Nitric oxide Xanthine oxidase Nitrite Polysulfide Hydrogen sulfide |
url |
http://www.sciencedirect.com/science/article/pii/S2213231719315885 |
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