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.

Genetic Polymorphisms of Endothelial Nitric Oxide Synthase Associated with Hypertension and Blood Homocysteine Levels

“… 36 Recent advances exemplifying the physiological role of NOS and the mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease have been proposed as therapeutic targets in cardiovascular disease. 37 Overall, the associations between these studies and our study can provide an important strategy in the therapeutic approach for hypertension related to improved NOS activity and nutritional supplementation with folate and vitamin B12 to reduce the risk of hyperhomocysteinemia. However, this study has several limitations.…”

Lutein Attenuates Isoproterenol-Induced Cardiac Hypertrophy in Rats

“…Dysfunctional NO pathway is also involved in the pathogenesis of CH (Roy et al 2023). Therefore, we used L-NAME, a nitric oxide synthase (NOS) inhibitor (Ishikawa et al to explore the role of NO in the benefits of LUT.…”

A Comprehensive Retrospective Study on the Mechanisms of Cyclic Mechanical Stretch-Induced Vascular Smooth Muscle Cell Death Underlying Aortic Dissection and Potential Therapeutics for Preventing Acute Aortic Aneurysm and Associated Ruptures

“…NO is regarded as a major and potent mediator of vasodilation. Low amounts of NO generated in cells promote cardiovascular homeostasis, whereas excessive NO levels may be deleterious to the cardiovascular system and contribute to hypertension [ 100 ]. Thus, we suggest that CMS stimulates iNOS expression and NO production in RASMCs, thereby protecting them from CMS-induced cell death in the early stages.…”