Katrina M Miranda

Associate Professor, Chemistry and Biochemistry-Sci

Associate Professor, BIO5 Institute

Primary Department

Chemistry & Biochemistry

Department Affiliations

Chemistry & Biochemistry

BIO5 Institute

Contact

(520) 626-3655

kmiranda@arizona.edu

Work Summary

We seek to produce new drugs that harness molecules produced during the natural immune response in order to treat cancer and pain. Such compounds may also provide new treatments for heart failure and alcoholism.

Research Interest

Katrina Miranda, PhD, claims nitric oxide (NO), which is synthesized in the body via enzymatic oxidation of L-arginine, is critical to numerous physiological functions, but also can contribute to the severity of diseases such as cancer or pathophysiological conditions such as stroke. This diversity in the responses to NO biosynthesis is a reflection of the diverse chemistry of NO. For instance, NO can alter the function of enzymes by binding to metal centers. This type of interaction could result in outcomes as disparate as control of blood pressure or death of an invading bacterium. NO can also be readily converted to higher nitrogen oxides such as N2O3 or ONOOH, which have very different chemical and biological properties. The ultimate result will depend upon numerous factors, particularly the location and concentration of NO produced. Therefore, site-specific modulation of NO concentration offers intriguing therapeutic possibilities for an ever expanding list of diseases, including cancer, heart failure and stroke. As a whole, Dr. Miranda is interested in elucidating the fundamental molecular redox chemistry of NO and in developing compounds to deliver or scavenge NO and other nitrogen oxides. These projects are designed to answer questions of potential medical importance through a multi-disciplinary approach, including analytical, synthetic, inorganic and biochemical techniques.The project categories include five major disciplines. First, she will work on the development and utilization of analytical techniques for detection and measurement of NO and other nitrogen oxides as well as the resultant chemistry of these species. Second, she will synthesize potential donors or scavengers of NO and other nitrogen oxides. Third, it’s necessary to describe chemical characterization of these compounds (spectroscopic features, kinetics, mechanisms and profiles of nitrogen oxide release, etc.). Fourth, Dr. Miranda will try to describe the biological characterization of these compounds (assay of effects on biological compounds, mechanisms and pathways, in vitro determination of potential for therapeutic utility, etc.). Fifth, she will identify of potential targets, such as enzymes, for treatment of disease through exposure to nitrogen oxide donors. Keywords: cancer treatment, pain treatment

Publications

Orthogonal properties of the redox siblings nitroxyl and nitric oxide in the cardiovascular system: A novel redox paradigm

Wink, D. A., Miranda, K. M., Katori, T., Mancardi, D., Thomas, D. D., Ridnour, L., Espey, M. G., Feelisch, M., Colton, C. A., Fukuto, J. M., Pagliaro, P., Kass, D. A., & Paolocci, N. (2003). Orthogonal properties of the redox siblings nitroxyl and nitric oxide in the cardiovascular system: A novel redox paradigm. American Journal of Physiology - Heart and Circulatory Physiology, 285(6 54-6), H2264-H2276.

PMID: 12855429;Abstract:

Endogenous formation of nitric oxide (NO) and related nitrogen oxides in the vascular system is critical to regulation of multiple physiological functions. An imbalance in the production or availability of these species can result in progression of disease. Nitrogen oxide research in the cardiovascular system has primarily focused on the effects of NO and higher oxidation products. However, nitroxyl (HNO), the one-electron-reduction product of NO, has recently been shown to have unique and potentially beneficial pharmacological properties. HNO and NO often induce discrete biological responses, providing an interesting redox system. This article discusses the emerging aspects of HNO chemistry and attempts to provide a framework for the distinct effects of NO and HNO in vivo.

Positive inotropic and lusitropic effects of HNO/NO<sup>-</sup> in failing hearts: Independence from β-adrenergic signaling

Paolocci, N., Katori, T., Champion, H. C., E., M., Miranda, K. M., Fukuto, J. M., Wink, D. A., & Kass, D. A. (2003). Positive inotropic and lusitropic effects of HNO/NO^- in failing hearts: Independence from β-adrenergic signaling. Proceedings of the National Academy of Sciences of the United States of America, 100(9), 5537-5542.

PMID: 12704230;PMCID: PMC154380;Abstract:

Nitroxyl anion (HNO/NO^-), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO/NO^- augments systolic and diastolic function of failing hearts, and whether contrary to NO/nitrates such modulation enhances rather than blunts β-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO/NO^- generated by Angelis' salt (AS) was infused (10 μg/kg per min, i.v.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine(DEA)/NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed β-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA/NO blunted β-stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA/NO or NTG, supporting a proposed role of this peptide to HNO/NO^- cardiotropic action. Thus, HNO/NO^- has positive inotropic and lusitropic action, which unlike NO/nitrates is independent and additive to β-adrenergic stimulation and stimulates CGRP release. This suggests potential of HNO/NO^- donors for the treatment of heart failure.

Mechanism of pH-dependent decomposition of monoalkylamine diazeniumdiolates to form HNO and NO, deduced from the model compound methylamine diazeniumdiolate, density functional theory, and CBS-QB3 calculations

Dutton, A. S., Suhrada, C. P., Miranda, K. M., Wink, D. A., Fukuto, J. M., & Houk, K. N. (2006). Mechanism of pH-dependent decomposition of monoalkylamine diazeniumdiolates to form HNO and NO, deduced from the model compound methylamine diazeniumdiolate, density functional theory, and CBS-QB3 calculations. Inorganic Chemistry, 45(6), 2448-2456.

PMID: 16529464;PMCID: PMC3164114;Abstract:

Isopropylamine diazeniumdiolate, IPA/NO, the product of the reaction of isopropylamine and nitric oxide, NO, decomposes in a pH-dependent manner to afford nitroxyl, HNO, in the pH range of 13 to above 5, and NO below pH 7. Theoretical studies using B3LYP/6-311+G(d) density functional theory, the polarizable continuum and conductor-like polarizable continuum solvation models, and the high-accuracy CBS-QB3 method on the simplified model compound methylamine diazeniumdiolate predict a mechanism involving HNO production via decomposition of the unstable tautomer MeNN⁺(O^-)NHO ^-. The production of NO at lower pH is predicted to result from fragmentation of the amide/NO adduct upon protonation of the amine nitrogen. © 2006 American Chemical Society.

Donors of HNO

Miranda, K. M., Nagasawa, H. T., & Toscano, J. P. (2005). Donors of HNO. Current Topics in Medicinal Chemistry, 5(7), 649-664.

PMID: 16101426;Abstract:

Recent comparisons of the pharmacological effects of nitric oxide (NO) and nitroxyl (HNO) donors have demonstrated that the responses to these redox-related nitrogen oxides are nearly universally dissimilar. These analyses have suggested the existence of mutually exclusive signaling pathways as a result of discrete chemical interactions of HNO and NO with a variety of critical biomolecules. Although the mechanisms of action are currently unresolved, the pharmacological responses to HNO are promising for clinical treatment of cardiovascular diseases such as heart failure, myocardial infarction and stroke. This review provides a detailed discussion of the most commonly utilized donors of HNO as well as a guideline for the characterization of novel donors. © 2005 Bentham Science Publishers Ltd.

The emergence of nitroxyl (HNO) as a pharmacological agent

Switzer, C. H., Flores-Santana, W., Mancardi, D., Donzelli, S., Basudhar, D., Ridnour, L. A., Miranda, K. M., Fukuto, J. M., Paolocci, N., & Wink, D. A. (2009). The emergence of nitroxyl (HNO) as a pharmacological agent. Biochimica et Biophysica Acta - Bioenergetics, 1787(7), 835-840.

PMID: 19426703;PMCID: PMC2761033;Abstract:

Once a virtually unknown nitrogen oxide, nitroxyl (HNO) has emerged as a potential pharmacological agent. Recent advances in the understanding of the chemistry of HNO has led to the an understanding of HNO biochemistry which is vastly different from the known chemistry and biochemistry of nitric oxide (NO), the one-electron oxidation product of HNO. The cardiovascular roles of NO have been extensively studied, as NO is a key modulator of vascular tone and is involved in a number of vascular related pathologies. HNO displays unique cardiovascular properties and has been shown to have positive lusitropic and ionotropic effects in failing hearts without a chronotropic effect. Additionally, HNO causes a release of CGRP and modulates calcium channels such as ryanodine receptors. HNO has shown beneficial effects in ischemia reperfusion injury, as HNO treatment before ischemia-reperfusion reduces infarct size. In addition to the cardiovascular effects observed, HNO has shown initial promise in the realm of cancer therapy. HNO has been demonstrated to inhibit GAPDH, a key glycolytic enzyme. Due to the Warburg effect, inhibiting glycolysis is an attractive target for inhibiting tumor proliferation. Indeed, HNO has recently been shown to inhibit tumor proliferation in mouse xenografts. Additionally, HNO inhibits tumor angiogenesis and induces cancer cell apoptosis. The effects seen with HNO donors are quite different from NO donors and in some cases are opposite. The chemical nature of HNO explains how HNO and NO, although closely chemically related, act so differently in biochemical systems. This also gives insight into the potential molecular motifs that may be reactive towards HNO and opens up a novel field of pharmacological development.

Katrina M Miranda