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HNO/Thiol Biology as a Therapeutic Target

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Abstract

Nitroxyl (HNO) is a protonated, one-electron reduction product of nitric oxide (NO) with distinct biological effects. Like NO, HNO exerts vasodilatory effects and inhibits platelet aggregation but unlike NO, it stimulates the release of the strongest known vasodilator, calcitonin gene-related peptide and, more importantly, it reacts with thiols to eventually lead to their oxidation to disulfides. It became clearer in recent years that it is this particular chemical property that holds the key to the great pharmacological potential of the HNO donors; the treatment of the heart failure being the best example. The emergence of hydrogen sulfide (H2S), a new gaseous signaling molecule with physiological and pharmacological effects overlapping with those of NO (and HNO), led to some interesting discoveries suggesting the important role of the NO/H2S crosstalk in the endogenous generation of HNO, but also opening up some new perspective for the use of this chemistry as pharmacological substitute for the HNO donors. This book chapter summarizes all recent advancements in the field of HNO (bio)chemistry and pharmacology.

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Abbreviations

AC:

Adenylate cyclase

AS:

Angeli’s salt

ALDH:

Aldehyde dehydrogenase

cAMP:

Cyclic adenosine monophosphate

CBS:

Cystathionine beta synthase

cGMP:

Cyclic guanosine monophosphate

CGRP:

Calcitonin gene-related peptide

CHF:

Congestive heart failure

CLR:

Calcitonin receptor-like receptor

CSE:

Cystathionine gamma lyase

CuZnSOD:

Cooper zinc superoxide dismutase

DTT:

Dithiothreitol

EDHF:

Endothelium derived hyperpolarizing factor

EDRF:

Endothelium-derived relaxing factor

FeSOD:

Iron superoxide dismutase

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GSH:

Glutathione

IPA/NO:

Isopropylamine diazeniumdiolate

IR:

Ischemia/reperfusion

MHC:

Myosin heavy chain

MLC1:

Myosin light chain

MnSOD:

Manganese superoxide dismutase

NMDA:

N-methyl-d-aspartate receptor

NOS:

Nitric oxide synthase

PKA:

Protein kinase A

PLN:

Phospholamban

RAMP:

Receptor activity modifying protein

RyR:

Ryanodine receptor

SERCA2a:

Sarcoplasmic reticulum Ca2+ ATPase

sGC:

Soluble guanylate cyclase

SNP:

Sodium nitroprusside

TRPA1:

Transient receptor potential ankyrin 1

VSMC:

Vascular smooth muscle cells

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Acknowledgment

The authors would like to thank professors Ivana Ivanovic-Burmazovic (FAU Erlangen-Nuremberg) and Vesna Niketic (University of Belgrade) for careful reading of the manuscript and helpful discussions. We are also grateful to the Friedrich-Alexander University Erlangen-Nuremberg (Emerging Field Initiative, MRIC) and to the French State in the frame of the ”Investments for the future” Programme IdEx Bordeaux, reference ANR-10-IDEX-03-02.

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  1. Department of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg, Egerlandstrasse 1, Erlangen, 91058, Germany

    Jan Lj. Miljkovic & Milos R. Filipovic

  2. Universite de Bordeaux, IBGC, UMR 5095, F-33077, Bordeaux, France

    Milos R. Filipovic

  3. CNRS, IBGC, UMR 5095, F-33077, Bordeaux, France

    Milos R. Filipovic

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  1. Jan Lj. Miljkovic
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Correspondence to Milos R. Filipovic .

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  1. Duke University School of Medicine, Durham, North Carolina, USA

    Ines Batinić-Haberle

  2. Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil

    Júlio S. Rebouças

  3. Duke University School of Medicine, Durham, North Carolina, USA

    Ivan Spasojević

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Miljkovic, J.L., Filipovic, M.R. (2016). HNO/Thiol Biology as a Therapeutic Target. In: Batinić-Haberle, I., Rebouças, J., Spasojević, I. (eds) Redox-Active Therapeutics. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-30705-3_14

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