Vasoprotective Actions of the Novel Redox sSgnalling Molecule, Nitroxyl (HNO) - ICCAD 2017 - The 12th International Congress on Innovations in Coronary Artery Disease , 15-17 October, 2017 Venice, Italy

Introduction: Nitroxyl (HNO), the reduced and protonated congener of nitric oxide (NO^·), is a novel entity with distinct pharmacology and therapeutic advantages over NO^· (1). Unlike NO^·, HNO interacts directly with thiols to increase myocardial contractility, elevates plasma levels of calcitonin gene-related peptide and is resistant to scavenging by superoxide (^.O₂^-). Whilst these unique properties of HNO confer potential in the treatment of heart failure, our studies have also highlighted vasoprotective actions of HNO.
Aims: To investigate the vasoprotective actions of HNO donors in health and disease.
Methods: Vasoprotective actions of HNO were studied in models of hypertension and atherosclerosis.
Results: Our studies have shown that like NO^·, HNO donors serve as potent vasorelaxants (including human arteries) and inhibit platelet aggregation, mediating these effects predominantly via sGC activation and an elevation in cGMP. In contrast to NO^·, HNO donors are resistant to scavenging by ^.O₂^- and vascular tolerance development and target distinct vascular signaling pathways. We have shown that the vasoprotective (vasorelaxant, anti-aggregatory) actions of HNO are sustained in the setting of hypertension (SHR rat) and atherosclerosis (ApoE^-/- mouse), where endogenous NO^· bioavailability is reduced. Furthermore, HNO rapidly suppresses vascular ^.O₂^- generation from Nox2-NADPH oxidase, via a cGMP-independent action, limits vascular dysfunction (2) and has anti-inflammatory actions (3).
Discussion: HNO donors offer considerable advantages over traditional NO^· donors due to their preserved bioavailability in oxidative stress, lack of tolerance development and favourable vasoprotective properties and may provide innovative pharmacotherapy for the treatment of vascular disease.

(1) Bullen et al (2011) Antiox Redox Signal 14:1675-1686
(2) Miller et al (2013) Free Rad Biol Med 60:264-271
(3) Andrews et al (2016) Clin Sci 130:1629-1640