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Hypoxic Nitrite Reduction to Nitric Oxide: A Computational Modeling Approach
Start Date: 5/7/2018Start Time: 12:00 PM
End Date: 5/7/2018End Time: 2:00 PM

Event Description
BIOMED PhD Thesis Defense

Hypoxic Nitrite Reduction to Nitric Oxide: A Computational Modeling Approach

Yien Liu, PhD Candidate, School of Biomedical Engineering, Science and Health Systems, Drexel University

Dov Jaron, PhD, Calhoun Distinguished Professor of Engineering in Medicine, School of Biomedical Engineering, Science and Health Systems, Drexel University

Nitric oxide (NO) is a powerful paracrine signaling molecule that plays a critical role in regulating blood vessel tone and vascular homeostasis. Deficiencies in endothelial NO production have been implicated in many cardiovascular and neurodegenerative diseases. Nitrite has been shown to act as a storage pool for NO that is relatively inactive in normoxia, but enzymatically reduced in hypoxia to restore lost NO. Recent experiments have identified a growing number of therapeutic applications of nitrite such as reduction of hypertension and cytoprotection against ischemia/reperfusion injury, but the mechanisms involved are not fully understood. We developed mathematical models to systematically analyze three major nitrite reduction pathways and characterize their NO elevation capabilities in microcirculatory vessel and tissue systems under various physiological, therapeutic, and pathological conditions. We also developed a microvascular network model to determine the effect of NO bioavailability on smooth muscle cell tone and the pressure-flow response.

First, we determined how nitrite infused into the blood paradoxically induces vasodilation despite strong NO scavenging by hemoglobin. The role of N2O3 as a hypothesized stable intermediate for preserving blood nitrite-derived NO was analyzed using a single vessel mass transport model of a microcirculatory arteriole and surrounding tissue. Our model predicts that with hypoxia and moderate nitrite concentrations, the N2O3 pathway can significantly preserve the NO produced by hemoglobin nitrite reductase in red blood cells and elevate NO reaching the smooth muscle cells. Our model demonstrates a viable pathway for reconciling experimental findings of potentially beneficial effects of nitrite infusions despite previous models showing negligible NO elevation associated with hemoglobin nitrite reductase.

Second, we applied this single vessel approach to a cardiac model to determine the role of myocardium myoglobin in regulating NO bioavailability. Our model predicts that cardiac myoglobin plays contrasting roles of scavenging NO during normoxia, but significantly elevating tissue and smooth muscle cell NO in acute ischemic, hypoxic, or acidotic conditions. This NO could then be responsible for mitigating deleterious effects under ischemic conditions.

Third, we expanded the vessel model to characterize two major tissue nitrite reductases: aldehyde and xanthine oxidoreductase (AOR/XOR). This study focuses on ischemic and hypoxic conditions in the heart, liver, and kidney microcirculation, where AOR and XOR nitrite reduction have been shown to have therapeutically beneficial effects. Our mathematical model demonstrates that under extreme hypoxic conditions with acidic pH, endogenous nitrite levels can be sufficient in these organ systems to elicit a functionally significant increase in NO bioavailability.

Finally, we developed a dynamic computational model of a branching microcirculatory network with four representative classes of resistance vessels to predict the effect of endothelium-derived NO on the pressure-flow response. Our model links vessel scale biotransport simulations of NO and O2 delivery to a mechanistic model of autoregulation and myogenic tone in a simplified microvascular network. Our simulations predict the steady state and transient behavior of resistance vessels to perturbations in blood pressure including effects of NO bioavailability on vascular tone. Together, these models contribute towards understanding the importance of nitrite reduction as a compensatory pathway for lost NO and the role of nitrite-NO interactions in microvascular flow regulation.
Contact Information:
Name: Ken Barbee
Phone: 215-895-1335
Email: barbee@drexel.edu
Yien Liu
Bossone Research Center, Room 709, located at 32nd and Market Streets.
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