Exogenous NO Therapy for the Treatment and Prevention of Atherosclerosis

Abstract

Amyl nitrite was introduced in 1867 as the first molecule of a new class of agents for the treatment of angina pectoris. In the following 150 years, the nitric oxide pathway has been the subject of a number of pharmacological approaches, particularly since when this elusive mediator was identified as one of the most important modulators of vascular homeostasis beyond vasomotion, including platelet function, inflammation, and atherogenesis. While having potent antianginal and antiischemic properties, however, nitric oxide donors are also not devoid of side effects, including the induction of tolerance, and, as shown in the last decade, of oxidative stress and endothelial dysfunction. In turn, endothelial dysfunction is itself felt to be involved in all stages of atherogenesis, from the development of fatty streaks to plaque rupture and thrombosis. In the present review, we summarize the agents that act on the nitric oxide pathway, with a particular focus on their potentially beneficial antiatherosclerotic and unwanted pro-atherosclerotic effects.

Keywords: nitric oxide; nitric oxide donors; organic nitrates.

Figure 1

Redox-control in the NO Pathway. Redox-dependent pathways that regulate nitric oxide (NO) and vascular homeostasis. The endothelial nitric oxide synthase (eNOS) and the soluble guanylyl cyclase (sGC) present a number of redox switches, which act directly or indirectly (for instance, in the case of the 26S proteasome, which is activated via 3-nitrotyrosine (3NT) modification causing inactivation of the eNOS cofactor tetrahydrobiopterin (BH₄) synthase GTP-cyclohydrolase (GCH-1), and of BH4 recycling enzyme dihydrofolate reductase (DHFR). Oxidation of BH₄ causes a positive feedback mechanism leading to further oxidative stress. Red arrows indicate inhibition. In contrast, NO prevents proteasomal DHFR degradation via tyrosine nitration of the 26S proteasome. O2⁻: superoxide anion; -SNO: s-nitroso-thiols; -SOxH: oxidized thiol; -SSG: glutathione disulfide; ZnC: Zinc; pThyr: phosphorylated thyrosine.

Figure 2

Organic nitrates.

Figure 3

Nicorandil.

Figure 4

Molsidomine and SIN-1.