Cardiovascular Therapeutic Potential of the Redox Siblings, Nitric Oxide (NO•) and Nitroxyl (HNO), in the Setting of Reactive Oxygen Species Dysregulation

Barbara K. Kemp-Harper, Anida Velagic, Nazareno Paolocci, John D. Horowitz, Rebecca H. Ritchie

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Researchpeer-review

10 Citations (Scopus)

Abstract

Reactive oxygen species (ROS) dysregulation is a hallmark of cardiovascular disease, characterised by an imbalance in the synthesis and removal of ROS. ROS such as superoxide (•O2-), hydrogen peroxide (H2O2), hydroxyl (OH•) and peroxynitrite (ONOO-) have a marked impact on cardiovascular function, contributing to the vascular impairment and cardiac dysfunction associated with diseases such as angina, hypertension, diabetes and heart failure. Central to the vascular dysfunction is a reduction in bioavailability and/or physiological effects of vasoprotective nitric oxide (NO•), leading to vasoconstriction, inflammation and vascular remodelling. In a cardiac context, increased ROS generation can also lead to modification of key proteins involved in cardiac contractility. Whilst playing a key role in the pathogenesis of cardiovascular disease, ROS dysregulation also limits the clinical efficacy of current therapies, such as nitrosovasodilators. As such, alternate therapies are sought. This review will discuss the impact of ROS dysregulation on the therapeutic utility of NO• and its redox sibling, nitroxyl (HNO). Both nitric oxide (NO) and nitroxyl (HNO) donors signal through soluble guanylyl cyclase (sGC). NO binds to the Fe(II) form of sGC and nitroxyl possibly to both sGC heme and thiol groups. In the vasculature, nitroxyl can also signal through voltage-dependent (Kv) and ATP-sensitive (KATP) K+ channels as well as calcitonin gene-related peptide (CGRP). In the heart, HNO directly targets critical thiols to increase myocardial contractility, an effect not seen with NO. The qualitative effects via elevation of cGMP are similar, i.e. lusitropic in the heart and inhibitory on vasoconstriction, inflammation, aggregation and vascular remodelling. Of pathophysiological significance is the fact the efficacy of NO donors is impaired by ROS, e.g. through chemical scavenging of NO, to generate reactive nitrogen oxide species (RNOS), whilst nitroxyl is apparently not.

Original languageEnglish
Title of host publicationReactive Oxygen Species
Subtitle of host publicationNetwork Pharmacology and Therapeutic Applications
EditorsHarald H. H. W. Schmidt, Pietro Ghezzi, Antonio Cuadrado
Place of PublicationCham Switzerland
PublisherSpringer
Pages311-337
Number of pages27
Volume264
ISBN (Electronic)9783030685102
ISBN (Print)9783030685096
DOIs
Publication statusPublished - 2021

Publication series

NameHandbook of Experimental Pharmacology
PublisherSpringer
ISSN (Print)0171-2004
ISSN (Electronic)1865-0325

Keywords

  • Cardiovascular
  • Nitric oxide
  • Nitroxyl
  • Reactive oxygen species

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