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Unveiling The Interplay of Nitric Oxide Signaling and Physiological Thiols; Novel Insights

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title
Unveiling The Interplay of Nitric Oxide Signaling and Physiological Thiols; Novel Insights
author
Poudel, Laxman
abstract
Nitric oxide (NO) stands as a pivotal signaling molecule garnering significant research attention in the realm of cardiovascular health. Its crucial role in sustaining heart and blood vessel well-being is underscored by its ability to widen blood vessels, facilitating improved blood flow, and thwarting platelet activation and aggregation to stave off clot formation and vessel obstruction. Additionally, NO safeguards the integrity of vascular endothelial cells. Its production primarily stems from Nitric Oxide Synthases (NOS), including those housed within vascular endothelial cells, and through the reduction of nitrite by deoxyhemoglobin, converting it into Nitrosyl hemoglobin (HbNO).Yet, an intriguing paradox emerges within NO signaling: while it undertakes indispensable functions, its rapid scavenging by oxyhemoglobin swiftly converts it into nitrate, seemingly halting its signaling capabilities. This prompts a fundamental inquiry: how does NO manage to execute its signaling duties proficiently amidst this challenging physiological milieu? My thesis delves into my project’s trajectory leading to the identification of a novel molecule dubbed NO-ferroheme, derived from readily available physiological constituents. NO-ferroheme eludes scavenging by oxyhemoglobin, can transfer between different physiological media, and exhibits NO signaling attributes, potentially serving as a viable alternative for NO survival and signaling in physiology. I demonstrate that physiological thiol species like GSH and Hydrogen sulfide catalyze the rapid reaction of NO and heme, yielding NO-ferroheme—an unforeseen role of thiol species in NO signaling. Furthermore, my comparative analysis between GSH and sulfide reveals sulfide’s superiority in catalyzing the reaction when heme is in a protein-bound state, a scenario more akin to physiological conditions. Moreover, my investigation delves into a comparison of the rate of nitrite reduction by sickled and healthy red blood cells under two different oxygen saturations. Sickle cell hemoglobin (HbS), characterized by polymerization, exhibits a diminished rate of nitrite reduction in its polymer phase compared to healthy adult hemoglobin (HbA). However, its solution phase showcases a heightened rate of nitrite reduction. This confluence of rates results in no net disparity from HbA under both oxygen saturations, suggesting the potential therapeutic utility of Nitrite in sickle cell disease management.
subject
Cardiovascular
Nitric Oxide Signaling
Novel
Physiology
Therapeutic
Thiols
contributor
Kim-Shapiro, Daniel D (advisor)
Kim-Shapiro, Daniel D (committee member)
Zhu, Xuewei X (committee member)
Guthold, Martin M (committee member)
Salsbury, Freddie F (committee member)
Kandada, Ajay Ram A (committee member)
date
2024-05-23T08:36:22Z (accessioned)
2024 (issued)
degree
Physics (discipline)
embargo
2029-06-01 (terms)
2029-06-01 (liftdate)
identifier
http://hdl.handle.net/10339/109450 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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