Eric E. Kelley, Ph.D.
Dr. Kelley is a classically-trained redox biologist. He received his Ph.D. in Free Radical Biology at the University of Iowa (cancer background) and conducted his post-doctoral studies at the Center for Free Radical Biology at the University of Alabama at Birmingham (cardiovascular background). After serving as faculty in the Department of Anesthesiology and Director of the Vascular Medicine Institute’s Free Radical Facility at the University of Pittsburgh (cardiopulmonary/obesity background), he joined the Department of Physiology and Pharmacology here at WVU where he will continue to pursue redox-related aims in the context of obesity/diabetes as well as cancer.
The sphere of interest:
Dr. Kelley has spent the past 13 years exploring the impact of reactive species and free radicals on vascular inflammation as well as redox-mediated signaling in obesity/diabetes. Specifically, he has focused on a critical enzymatic source of oxidants, xanthine oxidoreductase (XOR) which catalyzes the oxidation of hypo/xanthine to form uric acid (UA) while reducing O2 to reactive oxygen species (ROS), O2●- and H2O2. Both ROS and UA have been implicated in the pathogenesis of the metabolic abnormalities of obesity; insulin resistance, dyslipidemia/steatosis, and cardiovascular disease. However, the contribution of XOR to metabolic dysregulation has not been investigated. Notably, from a therapeutic standpoint, XOR is an outstanding drug target, since the capacity to effectively alter the activity of other contributors to obesity-related oxidative stress (e.g. NADPH oxidase, mitochondria, uncoupled nitric oxide synthase, etc.) is limited or nonexistent. Conversely, XOR inhibitors are FDA-approved for the treatment of gout and thus have the potential to be rapidly translatable to off-label clinical applications.
In addition to being a source of both ROS and UA, under hypoxic/inflammatory conditions XOR can catalyze the one electron reduction of nitrate (NO3-) to nitrite (NO2-) and nitrite to nitric oxide (●NO). As such, XOR can serve as a source of salutary ●NO under conditions similar to those that mediate significant reduction in the enzymatic activity of nitric oxide synthase (NOS). With this in mind, Dr. Kelley is also actively pursuing the hypothesis that pharmacologic supplementation with nitrite can be used to manipulate XOR-derived product formation to favor ●NO production at the expense of oxidant generation. Using tissue-specific XOR knockouts, he is currently examining the resultant impact on beneficial actions attributable to nitrite treatment and the mechanisms underpinning these processes.
While Dr. Kelley’s focus has been centered on metabolic and cardiovascular disease, he is currently expanding his sphere of interest by reverting to his graduate training in cancer biology and electron paramagnetic resonance (EPR). Specifically he is interested in: 1) defining the impact of post-translation modifications of XOR on electron flux and alteration of product identity, 2) characterizing normal and tumor tissue oxygenation to map anatomic sites where XOR may mediate responses and 3) examining the mechanisms driving down-regulation of XOR expression/activity in tumor cells, an environment that is otherwise conducive to up-regulation of XOR in non-neoplastic cells.
Selected publications:
- Kotlarczyk, M.P., Billard, M., Green, B.R., Hill, J.C., Shiva, S., Kelley, E.E., Phillippi, J.A., Gleason, T. Regional Disruptions in Endothelial Nitric Oxide Pathway Associated With Bicuspid Aortic Valve. Ann Thorac Surg. [Epub ahead of print] Jun, 2016.
- Khoo, N.K., Cantu-Medellin, N., St Croix, C.M. and Kelley, E.E. In vivo immuno-spin trapping: Imaging the footprints of oxidative stress. Curr Protoc Cytom. 74:12.42.1-12, 2015.
- Kelley, E.E. Dispelling dogma and misconceptions regarding the most pharmacologically targetable source of reactive species in inflammatory disease, xanthine oxidoreductase. Arch Toxicol, 89(8):1193-207, 2015.
- Weidert E.R., Schoenborn, S.O., Cantu-Medellin, N., Coughoule, K.V., Jones, J.P. and Kelley, E.E. Inhibition of xanthine oxidase by the aldehyde oxidase inhibitor raloxifene: Implications for identifying molybdopterin nitrite reductases. Nitric Oxide, 37C:41-45, 2014.
- King, A.L., Polhemus, D.J., Bhushan, S., Otsuka, H., Kondo, K., Nicholson, C., Bradley, J.M., Islam, K.N., Calvert, J.W., Y., Dugas, T.R., Kelley, E.E., Elrod, J.W., Wang, R., and Lefer, D.J. Endothelial Nitric Oxide Synthase (eNOS) Regulation by Cystathione Gamma Lyase (CSE): Crosstalk Between Hydrogen Sulfide (H2S) and Nitric Oxide (NO) Signaling Pathways. Proc Natl Acad Sci USA, 111(8):3182-7, 2014.
- Kelley, E.E., Baust, J., Gor, S., Cantu-Medellin, N., Devlin, J.E., St. Croix, C.M., Champion, H.C., Freeman, B.A., and Khoo, N.K.H. Inhibition of Obesity-induced Pulmonary Arterial Hypertension by Fatty Acid Nitroalkene Derivatives. Cardiovasc Res, 101(3):352-63, 2014. PMID: 24385344.
- Cantu-Medellin, N. and Kelley, E.E. Xanthine oxidoreductase-catalyzed reactive species generation: A process in critical need of reevaluation. Redox Biol, 1(1):353-358, 2013.
- Cantu-Medellin, N. and Kelley, E.E. Xanthine oxidoreductase-catalyzed reduction of nitrite to nitric oxide: Insights regarding where, when and how. Nitric Oxide, 34:19-26, 2013.
- Khoo, N.K., Cantu-Medline, N., Fleming, A.M., Champion, H.C., Devlin, J.E., Watkins, S., Mason, R.P., Freeman, B.A. and Kelley, E.E. Obesity-induced tissue free radical formation: an immunospin trapping study. Free Radic Biol Med, 52:2312–2319, 2012.