Strategies to increase nitric oxide signalling in cardiovascular disease

Abstract

Nitric oxide (NO) is a key signalling molecule in the cardiovascular, immune and central nervous systems, and crucial steps in the regulation of NO bioavailability in health and disease are well characterized. Although early approaches to therapeutically modulate NO bioavailability failed in clinical trials, an enhanced understanding of fundamental subcellular signalling has enabled a range of novel therapeutic approaches to be identified. These include the identification of: new pathways for enhancing NO synthase activity; ways to amplify the nitrate-nitrite-NO pathway; novel classes of NO-donating drugs; drugs that limit NO metabolism through effects on reactive oxygen species; and ways to modulate downstream phosphodiesterases and soluble guanylyl cyclases. In this Review, we discuss these latest developments, with a focus on cardiovascular disease.

Modulated nitric oxide delivery in three-dimensional biomaterials for vascular functionality

“…Molecular oxygen [8] and nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) [9] are involved in the reaction as the co-substrates. The reaction relies on three NO synthase (NOS) isoforms: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) with different regulation and activities (Reaction mechanisms for these NOS reviewed by Lundberg et al [3] ). The nNOS and eNOS form a constitutive class that is regulated by calcium (Ca while iNOS mostly found in macrophages, neutrophils, fibroblasts, and hepatocytes, which is activated immunologically by exposure to bacterial endotoxin or cytokines, [10] with less dependence on intracellular Ca 2+ levels.…”

“…Besides these factors, NO production is also regulated by the presence of agonists and stimuli like fluid shear stress and pathogens. [11] It has been suggested that NO-signaling pathways can be up-regulated by both physical exercise and certain dietary components [3] . Straub et al have demonstrated the existence of another pathway involving deoxygenated globins for NO production in human endothelial cells (ECs).…”

“…[3] These pathways possess distinct reaction speeds, with only picomolar or nanomolar NO required for the activation of soluble guanylate cyclase (sGC) and triggering radical-radical reactions. However, the effects of NO on cell responses are dose-dependent.…”

“…[2] Various disease and lifestyle factors for cardiovascular diseases (CVDs) are associated with NO-signaling pathways ( Fig. 1), [3] and benefits from the mostly acceptable lifestyles and cardiovascular therapies are due to the release of NO. Therapeutic approaches for CVDs emerging over the past 10 years have been proposed to target both the upstream and downstream of NO-signaling pathways.…”

The Effect of Acute and Chronic Moderate and High Intensity Aerobic Exercise on Serum Nitric Oxide in Untrained Overweight Males

“…Although endothelial dysfunction is a strong predictor for cardiovascular disease, it reduces the repair of arterial hemostasis (12,15,16). By doing aerobic exercise regularly, NOS makes NO continuous release, which definitely improved the control of arterial blood pressure by relaxing the smooth muscle cells (11).…”