Chen K, Popel AS. Nitric oxide production pathways in erythrocytes and plasma

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Biorheology (Impact Factor: 1.18). 02/2009; 46(2):107-19. DOI: 10.3233/BIR-2009-0531
Source: PubMed


Nitric oxide (NO) is a potent regulator of vascular tone and hemorheology. The signaling function of NO was largely unappreciated until approximately 30 years ago, when the endothelium-derived relaxing factor (EDRF) was identified as NO. Since then, NO from the endothelium has been considered the major source of NO in the vasculature and a contributor to the paracrine regulation of blood hemodynamics. Because NO is highly reactive, and its half-life in vivo is only a few seconds (even less in the bloodstream), any NO bioactivity derived from the intraluminal region has traditionally been considered insignificant. However, the availability and significance of NO signaling molecules derived from intraluminal sources, particularly erythrocytes, have gained attention in recent years. Multiple potential sources of NO bioactivity have been identified in the blood, but unresolved questions remain concerning these proposed sources and how the NO released via these pathways actually interacts with intravascular and extravascular targets. Here we review the hypotheses that have been put forward concerning blood-borne NO and its contribution to hemorheological properties and the regulation of vascular tone, with an emphasis on the quantitative aspects of these processes.

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Available from: Aleksander S Popel
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    • "Various factors are likely to regulate the role of ATP in vasodilatation such as the activity of transporters that regulate ATP release, enzymes that regulate ATP concentrations and purinergic receptor expression levels [17]. The NO (or NOx) based hypotheses can be further subdivided into those that depend on the scavenging of endothelia-generated or more recently RBC-eNOS-generated NO [18] [19] [20] [21] to yield S-nitrosohemoglobin (SNO-Hb) or those that transform nitrite to NO within the RBC by hemoglobin acting as a nitrite reductase. In the SNO-Hb hypothesis, deoxygenated Hb in its T-state scavenges Contents lists available at SciVerse ScienceDirect journal homepage: "
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    ABSTRACT: Protein disulfide isomerase (PDI) is an abundant protein primarily found in the endoplasmic reticulum and also secreted into the blood by a variety of vascular cells. The evidence obtained here, suggests that PDI could directly participate in the efflux of NO(+) from red blood cells (RBC). PDI was detected both in RBC membranes and in the cytosol. PDI was S-nitrosylated when RBCs were exposed to nitrite under ∼50% oxygen saturation but not under ∼100% oxygen saturation. Furthermore, it was observed that hemoglobin (Hb) could promote PDI S-nitrosylation in the presence of ∼600 nM nitrite. In addition, three lines of evidence were obtained for PDI-Hb interactions: (1) Hb co-immunoprecipitated with PDI; (2) Hb quenched the intrinsic PDI fluorescence in a saturable manner; and (3) Hb-Fe(II)-NO absorption spectrum decreased in a [PDI]-dependent manner. Finally, PDI was detected on the surface RBC under ∼100% oxygen saturation and released as soluble under ∼50% oxygen saturation. The soluble PDI detected under ∼50% oxygen saturation was S-nitrosylated. Based on these data it is proposed that PDI is taken up by RBC and forms a complex with Hb. Hb-Fe(II)-NO that is formed from nitrite reduction under ∼50% O2, then transfers NO(+) to either Hb-Cys β93 or directly to PDI resulting in S-nitroso-PDI which transverses the RBC membrane and attaches to the RBC surface. When RBCs enter tissues the S-nitroso-PDI is released from the RBC-surface into the blood where its NO(+) is transferred into the endothelium thereby inducing vasodilation, suggesting local oxygen-dependent dynamic interplays between nitrite, NO and S-nitrosylation.
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    ABSTRACT: The purpose of this review is to highlight recent publications examining nitric oxide production in health and disease and its association with clinical nutrition and alterations in metabolism. The role of the cofactor tetrahydrobiopterin in nitric oxide production and its relation with arginine availability is indicated as an important explanation for the arginine paradox. This offers potential for nitric oxide regulation by dietary factors such as arginine or its precursors and vitamin C. Because diets with a high saturated fat content induce high plasma fatty acid levels, endothelial nitric oxide production is often impaired due to a reduction in nitric oxide synthase 3 phosphorylation. Increasing the arginine availability by arginine therapy or arginase inhibition was, therefore, proposed as a potential therapy to treat hypertension. Recent studies in septic patients and transgenic mice models found that inadequate de-novo arginine production from citrulline reduces nitric oxide production. Citrulline supplementation may, therefore, be a novel therapeutic approach in conditions of arginine deficiency. Both lack and excess of nitric oxide production in diseases can have various important implications in which dietary factors can play a modulating role. Future research is needed to expand our understanding of the regulation and adequate measurement of nitric oxide production at the organ level and by the different nitric oxide synthase isoforms, also in relation to clinical nutrition.
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