Inorganic nitrite bioactivation and role in physiological signaling and therapeutics

The bioactivation of inorganic nitrite refers to the conversion of otherwise 'inert' nitrite to the diatomic signaling molecule nitric oxide (NO), which plays important roles in human physiology and disease, notably in the regulation of vascular tone and blood flow. While the most well-known sources of NO are the nitric oxide synthase (NOS) enzymes, another source of NO is the nitrate-nitrite-NO pathway, whereby nitrite (obtained from reduction of dietary nitrate) is further reduced to form NO. The past few decades have seen extensive study of the mechanisms of NO generation through nitrate and nitrite bioactivation, as well as growing appreciation of the contribution of this pathway to NO signaling in vivo. This review, prepared for the volume 400 celebration issue of Biological Chemistry, summarizes some of the key reactions of the nitrate-nitrite-NO pathway such as reduction, disproportionation, dehydration, and oxidative denitrosylation, as well as current evidence for the contribution of the pathway to human cardiovascular physiology. Finally, ongoing efforts to develop novel medical therapies for multifarious conditions, especially those related to pathologic vasoconstriction and ischemia/reperfusion injury, are also explored.