BS (Biomedical Sciences and Chemistry), Unviersity of South Alabama, 1999. PhD (Cellular and Molecular Pathology), University of Alabama at Birmingham, 2004.
Dr. Shiva’s lab focuses on the mechanisms by which reactive nitrogen species (particularly nitrite and nitric oxide) regulate mitochondrial function during hypoxia and ischemia, the factors that influence this regulation and the implications of this regulation on pathology such as ischemia/ reperfusion injury.
Active projects in her lab include:
The role of heme proteins in regulating nitrite-dependent modulation of mitochondrial respiration. The anion nitrite (NO2-) is an endocrine storage form of nitric oxide (NO) in blood and tissues that can be reduced to bioavailable NO by heme proteins in conditions of low oxygen. In blood, the reduction of nitrite by hemoglobin mediates hypoxic vasodilation. We are interested in understanding how tissue nitrite reductases regulate mitochondrial function. Specifically, myoglobin, when deoxygenated, can efficiently reduce nitrite to NO and this NO subsequently inhibits mitochondrial respiration by binding to complex IV of the mitochondrial respiratory chain. We are interested in other ways that this interaction between nitrite and myoglobin regulates mitochondrial function as well as characterizing the physiological interplay between mitochondria and myoglobin with nitrite/NO acting as a signaling molecule linking the two.
The regulation of mitochondrial function by nitrite during ischemia/reperfusion. Low concentrations of nitrite have been shown to mediate cytoprotection in a number of models of ischemia/reperfusion of the brain, liver, heart and kidney. However, the mechanism of this cytoprotection is not known. The mitochondria play a central role in the progression of ischemia/reperfusion injury. Hence, we are interested in how nitrite regulates mitochondrial function during ischemia/reperfusion.
We have recently demonstrated that nitrite administered to animals before or during ischemia/reperfusion modulates mitochondrial function by S-nitrosating thiols on mitochondrial complex I, which leads to decreased reactive oxygen species generation, less oxidative damage of mitochondrial proteins, and prevention of cytochrome c release. We think that these modifications of function prevent mitochondrial dysfunction after reperfusion and lead to cytoprotection.
We are currently using isolated mitochondria, the Langendorff isolated and perfused heart, and in vivo ischemia/reperfusion models to further characterize nitrite-dependent cytoprotection, particularly in relation to other cytoprotective programs, such as ischemic preconditioning.
Mechanisms of nitrite generation and metabolism. Another focus of the lab is determining the mechanisms by which nitrite is formed and metabolized physiologically. Conventionally, nitrite is thought to be formed by the oxidation of nitric oxide. However, in vivo, the reaction of nitric oxide with oxygenated hemoglobin (which produces nitrate) is more kinetically favorable than the reaction with oxygen to produce nitrite. We have recently identified a role for the multicopper oxidase, ceruloplasmin, as an “NO oxidase” that can compete with the nitric oxide-hemoglobin reaction to oxidize NO to nitrite. We are currently further characterizing the role of ceruloplasmin in regulating nitrite levels in physiology and pathology, and in plasma and tissue.
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