Dysfunctional and Dysregulated Nitric Oxide Synthases in Cardiovascular Disease: Mechanisms and Therapeutic Potential

Abstract

Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, as well as the nitrate-nitrite-NO pathway. The three isoforms of NOS, namely neuronal (NOS1), inducible (NOS2), and endothelial (NOS3), have different localisation and functions in the human body, and are consequently thought to have differing pathophysiological roles. Furthermore, as we continue to develop a deepened understanding of the different roles of NOS isoforms in disease, the possibility of therapeutically modulating NOS activity has emerged. Indeed, impaired (or dysfunctional), as well as overactive (or dysregulated) NOS activity are attractive therapeutic targets in cardiovascular disease. This review aims to describe recent advances in elucidating the physiological role of NOS isoforms within the cardiovascular system, as well as mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease. We then discuss the modulation of NO and NOS activity as a target in the development of novel cardiovascular therapeutics.

Keywords: NOS inhibitor; cardiovascular disease; endothelial NOS; inducible NOS; neuronal NOS; nitric oxide synthase.

Figure 1

Overview of conditions with evidence for dysfunctional and dysregulated NOS activity. HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction.

Figure 2

Mechanism of nNOS inhibition in post-stroke glutamate excitotoxicity: Cerebral ischaemia leads to an increase in release of the excitatory neurotransmitter glutamate. Glutamate activates the N-methyl-D-aspartate receptor (NMDA-R), with subsequent influx of calcium (Ca²⁺) (and sodium, Na⁺). Excess Ca²⁺ within the neuron contributes to the generation of superoxide (•O₂⁻), which reacts with nitric oxide (NO) to generate peroxynitrite (ONOO⁻). Furthermore, neuronal nitric oxide synthase (nNOS) is bound to the NMDA-R by the postsynaptic density protein 95 (PSD95), forming a death-inducing signalling complex (DISC). This cascade leads to neuronal cell death via a number of mechanisms, including increased oxidative stress, mitochondrial dysfunction, and S-nitrosylation. Selective nNOS inhibition may provide a mechanism to interrupt this detrimental signalling cascade. Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.