Year: 2008
Type: dissertation
Abstract: Red blood cell-dependent hypoxic\nvasodilation is largely mediated via the delivery of NO through S-nitrosohemoglobin\n(Hb-SNO). Hb-SNO is regulated through allosteric and redox mechanisms that are\nnot well understood. Part One of\nthis dissertation explores the biochemical features of Hb micropopulations\nsuggested to be involved in Hb-SNO synthesis. An NO-liganded mixed valency\nmicropopulation was synthesized in vitro and identified\nspectroscopically as a ferric nitrosyl species (Fe(III)NO). Remarkably, this\nspecies was found to undergo a\nreaction that couples heme reduction and S-nitrosylation of β93C.\nThe biochemical properties of this species were found to resemble those of Hb\nvalency hybrids (VHy's) identified by others in previous work. The similarities between the two\nspecies are discussed, and a model for Hb-SNO formation, including the putative\nidentification of the intermediates involved, is proposed. Part Two explores\nthe insights provided by this chemistry as it is relevant to human pathophysiology\nin the context of Hb-SNO depletion of RBCs in stored blood. Hb-SNO and membrane S-nitrosothiols\nwere found to be depleted after only two days of storage. The vasoactive\nfunction of stored RBCs has been shown in previous work to be impaired relative\nto controls. These findings, in conjunction with the this study, could\nimplicate NO dysregulation as a primary component in the etiology of hypoxic\ndiseases and the negative sequelae associated with blood transfusions. The results\nfrom Part Two suggest that NO blood gas measurements could serve an important\nrole in improving clinical outcome of patients with hypoxic diseases. The goal of the work presented in Part\nThree is to begin to address this emerging need by developing an economical and\npragmatic sensor platform for routine clinical use in both an outpatient and\ninpatient setting.
Source: DukeSpace (Duke University)
Author: Michael Angelo
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2141973489