Mechanisms of nitrite reduction to nitric oxide in the heart and vessel wall

Abstract

Nitric oxide (NO) is an important regulator of a variety of biological functions, and also has a role in the pathogenesis of cellular injury. It had been generally accepted that NO is solely generated in biological tissues by specific nitric oxide synthases (NOS) which metabolize arginine to citrulline with the formation of NO. However, over the last 15 years, nitrite-mediated NO production has been shown to be an important mechanism of NO formation in the heart and cardiovascular system. Now numerous studies have demonstrated that nitrite can be an important source rather than simply a product of NO in mammalian cells and tissues and can be a potential vasodilator drug for cardiovascular diseases. There are a variety of mechanisms of nitrite reduction to NO and it is now appreciated that this process, while enhanced under hypoxic conditions, also occurs under normoxia. Several methods, including electron paramagnetic resonance, chemiluminescence NO analyzer, and NO-electrode have been utilized to measure, quantitate, and image nitrite-mediated NO formation. Results reveal that nitrite-dependent NO generation plays critical physiological and pathological roles, and is controlled by oxygen tension, pH, reducing substrates and nitrite levels. In this manuscript, we review the mechanisms of nitrite–mediated NO formation and the effects of oxygen on this process with a focus on how this occurs in the heart and vessels.

Dietary nitrate, nitric oxide, and restenosis

“…Furthermore, dietary tungsten (which inhibits XOR) also increased the severity of myointimal hyperplasia. These findings are consistent with previous observations that nitrite may be converted to NO in tissues and in blood, particularly in states of hypoxia and acidosis (12,13). Alternatively, or in addition, others have proposed that the bioactivation of nitrite to NO may involve hemoglobin, myoglobin, neuroglobin, aldehyde oxidase, carbonic anhydrase, eNOS, and mitochondrial enzymes, and in particular aldehyde dehydrogenase (14).…”

Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy

“…The NO 2 Ϫ anion can be readily reduced to bioactive NO along a physiological oxygen and pH gradient either nonenzymatically (167) or by a number of enzymes, including XORs, NOS, mitochondrial cytochromes, and deoxygenated hemoglobin and myoglobin (25,71,72,122,140). NO 2 Ϫ reduction to NO is enhanced under hypoxic conditions, which serves well its potential as a fast and potent pulmonary and systemic vasodilator drug and as a cytoprotective agent in I/R injury (166). The theoretical ease of the administration of NO 2 Ϫ anions makes it a potentially inter-esting drug candidate when NO bioavailability is low.…”

Nitrite reduction by xanthine oxidase family enzymes: a new class of nitrite reductases

“…In fact, nitrate and nitrite had long been regarded as merely inert end products of NO metabolism and of unfavourable dietary constituents. However, this ''dogma'' has been challenged by a growing number of independent studies showing that nitrite, under hypoxia and anoxia, can be reduced back to NO, in vitro, in situ and in vivo, and can act as a vasodilator, as a modulator of mitochondrial respiration and as a cytoprotector during in vivo postischaemia injury in a wide range of tissues [31][32][33][34][35]. Nitrite present in blood and other tissues has thus been viewed as an NO storage form that could be made available under conditions of hypoxia and anoxia to ensure cell survival.…”

“…The pathways of nitrite reduction to NO, extensively reviewed recently [31][32][33][34][35], include non-enzymatic disproportionation at low pH values, reduction by deoxyhaemoglobin or myoglobin, by mitochondrial cytochromes and cytochrome P 450 , and through the enzymatic conversion by XO and aldehyde oxidase. The in vivo relative importance of each of those ''nitrite-recycling'' pathways is difficult to evaluate, because it is determined by multifactoral aspects: the molecular oxygen concentration, the cellular pH and redox state, and the tissue type (which determines the concentration of enzyme, nitrite and available reducing substrates).…”

“…Interestingly, the mammalian aldehyde oxidase [29], another member of the XO family, was also recently shown to catalyse the nitrite reduction to NO [28,30]. This XOcatalysed and aldehyde oxidase catalysed nitrite reduction assumes particular importance owing to the amount of experimental evidence that points towards the participation of these two enzymes in the human in vivo formation of NO from nitrite (as was extensively and recently reviewed in [31][32][33][34][35]). However, in spite of these reactions being known for a while, the molecular mechanism of nitrate and nitrite reduction remains to be elucidated.…”