Oxidant-mediated impairment of nitric oxide signaling in sickle cell disease--mechanisms and consequences.
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.
Aslan
M
M
Department of Biochemistry, Akdeniz University Medical School, Antalya, Turkey.
Freeman
B A
BA
D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001120:Arginine / Q000627:therapeutic use; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D003598:Cytoskeletal Proteins; D005609:Free Radicals; D016877:Oxidants; D009569:Nitric Oxide; D001120:Arginine