The transfusion problem: role of aberrant S-nitrosylation

Abstract

Protein S-nitrosylation (the binding of a nitric oxide [NO] group to a cysteine thiol) is a major mechanism through which the ubiquitous cellular influence of NO is exerted. Disruption of S-nitrosylation is associated with a wide range of pathophysiologic conditions. Hemoglobin (Hb) exemplifies both of these concepts. It is the prototypical S-nitrosylated protein in that it binds, activates, and deploys NO. Within red blood cells (RBCs), Hb is S-nitrosylated during the respiratory cycle and thereby conveys NO bioactivity that may be dispensed to regulate local blood flow in the physiologic response known as hypoxic vasodilation. Hb thus both delivers oxygen directly and delivers vasoactivity to potentially optimize tissue perfusion in concert with local metabolic demand. Accordingly, decreased levels of S-nitrosylated Hb (also known as S-nitrosohemoglobin) and/or impaired delivery of RBC-derived NO bioactivity have been observed in a variety of disease states that are characterized by tissue hypoxemia. It has been shown recently that storage of blood depletes S-nitrosylated Hb, accompanied by reduced ability of RBCs to induce vasodilation. This defect appears to account in significant part for the impaired ability of banked RBCs to deliver oxygen. Renitrosylation can correct this impairment and thus may offer a means to ameliorate the disruptions in tissue perfusion produced by transfusion.

Figure

Blood Storage diminishes S-nitroso-hemoglobin (SNO-Hb) concentration, hypoxic vasodilation, and oxygen delivery (modified from references 39 and 44). A) Processing of donated blood under current AABB guidelines results in the loss of most SNO-Hb within 2 days and SNO-Hb levels remain low throughout the standard storage duration; B) The loss of SNO-Hb is pronounced after one day of storage and correlates directly with diminished hypoxic vasodilation by red blood cells (RBCs) in an in vitro bioassay (rabbit aortic ring segments).Vasorelaxation by RBCs is restored by repleting SNO-Hb; C) Consistent with diminished hypoxic vasodilation, peripheral tissue oxygen saturation in humans (measured with a trans-cutaneous probe placed on the thenar eminence) declines following transfusion with stored blood (21 days). D) Analysis of the effects on (canine) coronary artery blood flow produced by RBC infusion reveals that increases in flow elicited by re-nitrosylated RBCs were significantly greater than those produced by SNO-depleted (stored) RBCs, and that the degree of change was greater under hypoxic (5% fractional inspired oxygen; FiO₂) than normoxic (21% FiO₂) conditions. Thus, RBCs elicit vasodilation in vivo that is potentiated by hypoxia and dependent on SNO bioactivity, and RBCs depleted of SNO-Hb through storage can be re-nitrosylated to enhance blood flow (i.e., cardiac oxygen delivery).