Oxidant-mediated impairment of nitric oxide signaling in sickle cell disease--mechanisms and consequences

Abstract

In addition to its mediation of vascular relaxation and neurotransmission, nitric oxide (*NO) potently modulates oxygen radical reactions and inflammatory signaling. This participation of *NO in free radical and oxidative reactions will yield secondary oxides of nitrogen that display frequently-undefined reactivities and unique signaling properties. In sickle cell disease (SCD) inflammatory-derived oxidative reactions impair *NO-dependent vascular function. A combination of clinical and knockout-transgenic SCD mouse studies show increased rates of xanthine oxidase-dependent superoxide (O2*-) production and reveal the presence of an oxidative and nitrative inflammatory milieu in the sickle cell vasculature, kidney and liver. Considering the critical role of endothelial *NO production in regulating endothelial adhesion molecule expression, platelet aggregation, and both basal and stress-mediated vasodilation, the O2*- mediated reduction in *NO bioavailability can significantly contribute to the vascular dysfunction and organ injury associated with SCD.