The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management

Abstract

Reduced bioavailability of the nitric oxide (NO) signaling molecule has been associated with the onset of cardiovascular disease. One of the better-known and effective therapies for cardiovascular disorders is the use of organic nitrates, such as glyceryl trinitrate (GTN), which increases the concentration of NO. Unfortunately, chronic use of this therapy can induce a phenomenon known as "nitrate tolerance", which is defined as the loss of hemodynamic effects and a reduction in therapeutic effects. As such, a higher dosage of GTN is required in order to achieve the same vasodilatory and antiplatelet effects. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a cardioprotective enzyme that catalyzes the bio-activation of GTN to NO. Nitrate tolerance is accompanied by an increase in oxidative stress, endothelial dysfunction, and sympathetic activation, as well as a loss of the catalytic activity of ALDH2 itself. On the basis of current knowledge, nitrate intake in the diet would guarantee a concentration of NO such as to avoid (or at least reduce) treatment with GTN and the consequent onset of nitrate tolerance in the course of cardiovascular diseases, so as not to make necessary the increase in GTN concentrations and the possible inhibition/alteration of ALDH2, which aggravates the problem of a positive feedback mechanism. Therefore, the purpose of this review is to summarize data relating to the introduction into the diet of some natural products that could assist pharmacological therapy in order to provide the NO necessary to reduce the intake of GTN and the phenomenon of nitrate tolerance and to ensure the correct catalytic activity of ALDH2.

Keywords: aldehyde dehydrogenase 2 (ALDH2); endothelium; nitrate tolerance; nitrate–nitrite intake; nitric oxide (NO); oxidative stress.

Figure 1

Double control of the endothelium regarding ALDH2. Diagram (a) represents a functioning endothelium with a proper mitochondrial expression of the enzyme ALDH2, which has a protective action on the endothelium itself. On the other hand, in diagram (b) the dysfunctional endothelium determines the inhibition of the mitochondrial synthesis of ALDH2, with a consequent negative effect on the endothelium, which is undergoing an alteration of the oxidative state and the onset of inflammation.

Figure 2

The severity of nitrate tolerance and its effects.

Figure 3

Biogeochemical nitrogen cycle. The difficult assimilation of N2 makes it necessary to organify nitrogen. The first step is known as “nitrogen fixation”, in which N₂ is made available as ammonia (NH₃). A subsequent process known as “ammonification”, carried out by fungi and various soil bacteria, is responsible for the formation of the ammonium ion (NH₄⁺). Subsequently, this ion can be nitrified by some bacteria free in the soil, which generate nitrites and nitrates. Nitrates represent the most bioavailable form of nitrogen for plants, and they are absorbed at a radical level, transformed into vegetable proteins, and used as a source of nitrogen for the whole trophic network. The nitrogen cycle ends with the “denitrification” phase, in which some bacterial species again lead to the formation of N₂.

Figure 4

Processing of exogenous nitrates from food. Following exogenous dietary intake (1), most NO₃^- ions are absorbed by the stomach and duodenum. Furthermore, they undergo reduction reactions, stimulated by low pH values in these regions, which also leads to the formation of NO₂⁻ and NO (2). Subsequently, the nitrogen compounds are absorbed by systemic circulation (3), where there follows an increase in NO production and vasodilation (4). Finally, NO₃⁻ is normally excreted in the urine by the kidneys (5). In addition, a component of nitrates, concentrated in the salivary glands, undergoes a reduction induced by bacteria in the oral cavity and is transformed into nitrite and NO (6).

Figure 5

The protective and harmful roles of nitrogen compounds ingested through the diet. In diagram (a) the intake of plant products, which offer a large amount of nitrates, is shown. Subsequently, nitrates are transformed into nitrites and NO. The increased concentration of NO has beneficial effects on health, including vasodilation, reduction in blood pressure, better control of diabetes, better physical activities, reduction in muscle pain, and an improvement in the treatment of erectile dysfunction. In contrast, diagram (b) highlights the main effects from the intake of processed foods. The nitrites present in these foods can form toxic nitrosamines that are able to facilitate the onset of cancer, induce mutagenicity actions, alter biological macromolecules, and promote oxidative stress.