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Tracing the Path of Inhaled Nitric Oxide: Biological Consequences of Protein Nitrosylation
  • Vikram Bhatia,
  • Lara Elnagary,
  • Shyamala Dakshinamurti
Vikram Bhatia
University of Manitoba Children's Hospital Research Institute of Manitoba
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Lara Elnagary
University of Manitoba Children's Hospital Research Institute of Manitoba
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Shyamala Dakshinamurti
University of Manitoba College of Medicine
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Abstract

Nitric oxide (NO) is a comprehensive regulator of vascular and airway tone. Endogenous NO produced by nitric oxide synthases regulates multiple signaling cascades, including activation of soluble guanylate cyclase to generate cGMP, relaxing smooth muscle cells. Inhaled NO is an established therapy for pulmonary hypertension, especially in neonates, and has been recently proposed for treatment of hypoxic respiratory failure and acute respiratory distress syndrome due to COVID-19. In this review, we summarize the effects of endogenous and exogenous NO on protein S-nitrosylation, which is the selective and reversible covalent attachment of a nitrogen monoxide group to the thiol side chain of cysteine. This post-translational modification targets specific cysteines based on the acid/base sequence of surrounding residues, with significant impacts on protein interactions and function. S-nitrosothiol (SNO) formation is tightly compartmentalized and enzymatically controlled, but also propagated by non-enzymatic transnitrosylation of downstream protein targets. Redox-based nitrosylation and denitrosylation pathways dynamically regulate the equilibrium of SNO-proteins. We review the physiological roles of SNO proteins, including nitrosohemoglobin and autoregulation of blood flow through hypoxic vasodilation, and pathological effects of nitrosylation including inhibition of critical vasodilator enzymes; and discuss the intersection of NO source and dose with redox environment, in determining the effects of protein nitrosylation.

Peer review status:IN REVISION

08 Jul 2020Submitted to Pediatric Pulmonology
09 Jul 2020Assigned to Editor
09 Jul 2020Submission Checks Completed
10 Jul 2020Reviewer(s) Assigned
09 Aug 2020Review(s) Completed, Editorial Evaluation Pending
10 Aug 2020Editorial Decision: Revise Major