Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics

Abstract

The anion nitrite (NO(2)(-)) constitutes a biochemical reservoir for nitric oxide (NO). Nitrite reduction to NO may be catalyzed by hemoglobin, myoglobin or other metal-containing enzymes and occurs at increasing rates under conditions of physiologic hypoxia or ischemia. A number of laboratories have now demonstrated in animal models the ability of nitrite to provide potent cytoprotection following focal ischemia-reperfusion (IR) injury of the heart, liver, brain, and kidney. While the mechanism of nitrite-mediated cytoprotection remains to be fully characterized, the release of nitrite-derived NO following IR appears to be central to this mechanism. The evidence of nitrite-mediated cytoprotection against IR injury in multiple animal models opens the door to potential therapeutic opportunities in human disease. Here we review the mechanisms for nitrite formation in blood and tissue, its metabolic equilibrium with NO, nitrate, and NO-modified proteins, the evidence supporting nitrite-mediated cytoprotection, and the potential mechanisms driving cytoprotection, and we explore the opportunities for the therapeutic application of nitrite for human disease.

Figure 1. The NO-nitrite-nitrate pool

Nitrite (NO₂⁻) maintains a chemical equilibrium with its reduction product NO and its oxidation product nitrate (NO₃⁻). These reactions take place mainly in the bloodstream and the GI tract.

Figure 2. Mechanisms of nitrite-derived NO mediated cytoprotection

Nitrite may be reduced to NO by a variety of metal containing enzyme systems and the NO or the NO-modified proteins and lipids may in turn mediate cytoprotection against IR injury through any a variety of mechanisms. These mechanisms include: (A) S-nitrosation (and potentially N-nitrosation) of critical proteins involved in the signaling of apoptosis; (B) opening of mitochondrial K_ATP channels via the classic NO – cyclic guanidine monophosphate (cGMP) – protein kinase G (PKG) pathway which protects against cell death by preventing mitochondrial cytochrome c release, calcium overload and the opening of the mitochondrial permeability transition (MPT) pore; (C) Inhibition of complex I which reduces the direct production of reactive oxygen species (ROS) or the inhibition of complex IV which slows mitochondrial respiration and oxygen depletion during ischemia and thereby may minimize ROS production; (D) NO and NO-modified proteins have been associated with a variety of anti-inflammatory effects which minimize tissue injury after IR.