ANTIOXIDANTS & REDOX SIGNALING Volume 6, Number 6, 2004© Mary Ann Liebert, Inc. its complex interaction with NO has emerged (8, 13), including possibly the involvement of nitrite reduction to NO by deoxyHb in the vasodilation of human circulation (17). Previous spectral changes suggestive of heme redox reactions (10, 12) may actually be, as recent electron paramagnetic resonance evidence suggests, due in part to changes in the NO-heme geometry (7).

The interplay between NO and Hb, free or inside RBCs, therefore presented and continues to present a unique opportunity for researchers to explore the dynamics and physiological consequences of such reactions on both signaling and oxidative inflammatory events in human physiology. With this in mind, the current forum, Redox Biology of Blood, focuses on several aspects of signaling in blood with some exciting insights into the role of Hb in its redox communications with the vasculature. Yeh and Alayash (22) present data to show that cell-free Hb modulates key cell-signaling pathways by competing with biological peroxides that are required for the deactivation of the hypoxia-inducible factor, a transcriptional factor in endothelial cells subjected to hypoxia. These changes were shown to be more dependent on the protein redox rather than oxygen-carrying state. Reeder et al.(19) review the fundamentals of the radical and redox mechanisms of Hb and myoglobin “respiratory proteins” when these proteins are isolated from their normal reductant/antioxidant-rich environment with special emphasis on the prooxidant and pseudoperoxidase activity of these proteins under pathological conditions. Nagababu and Rifkind (16) remind us that heme, which is central to the hemoprotein functions in oxygen sensing, electron transport, signal transduction, and antioxidant defense mechanisms, is metabolically controlled by several enzymatic machineries. However, in the RBC, where the largest pool of heme proteins exists, no enzymatic degradative processes, such those outside RBCs, are operating. They showed that nonenzymatic heme degradation mechanisms are initiated within the red cell by the heme iron itself when it undergoes redox reactions in the presence of oxygen-producing reactive oxygen species. Bonaventura et al.(3) critically analyze the controversial “redox” and “allosteric” aspects of the physiological consequences of interactions of NO and Hb. The authors acknowledged that redox changes in the heme groups affect reactivity of the thiol groups on the protein and vice versa. In spite of the low levels of NO-Hb and SNO-Hb, these authors do not rule out participation of these species in NO-dependent signaling mechanisms. Crawford et al.(5) present a global role for the RBC in physiological mechanisms that may be controlling circulatory hemodynamics. They present current concepts surrounding this issue by addressing the question “How does the RBC control vascular function?” Buehler and Alayash (4) build on this concept and provide intriguing mechanisms by which RBCs can directly or indirectly communicate via redox intermediates with extravascular sites as part of a global oxygen-sensing mechanism. Tsai et al.(21) describe oxygen distribution and respiration by the microcirculation and provide data to show that tissue oxygenation requires the presence of oxygen delivery capacity and the control of oxygen consumption by the microvasculature. Baldwin (2) shows how, in microcirculation, this delicate balance can be disturbed when cell-free Hb, used as a “blood substitute” through heme-mediated redox reactions, can have far reaching