Redox-Regulation of α-Globin in Vascular Physiology.

Interest in the structure, function, and evolutionary relations of circulating and intracellular globins dates back more than 60 years to the first determination of the three-dimensional structure of these proteins. Non-erythrocytic globins have been implicated in circulatory control through reactions that couple nitric oxide (NO) signaling with cellular oxygen availability and redox status. Small artery endothelial cells (ECs) express free α-globin, which causes vasoconstriction by degrading NO. This reaction converts reduced (Fe 2+ ) α-globin to the oxidized (Fe 3+ ) form, which is unstable, cytotoxic, and unable to degrade NO. Therefore, (Fe 3+ ) α-globin must be stabilized and recycled to (Fe 2+ ) α-globin to reinitiate the catalytic cycle. The molecular chaperone α-hemoglobin-stabilizing protein (AHSP) binds (Fe 3+ ) α-globin to inhibit its degradation and facilitate its reduction. The mechanisms that reduce (Fe 3+ ) α-globin in ECs are unknown, although endothelial nitric oxide synthase (eNOS) and cytochrome b 5 reductase (CyB5R3) with cytochrome b 5 type A (CyB5a) can reduce (Fe 3+ ) α-globin in solution. Here, we examine the expression and cellular localization of eNOS, CyB5a, and CyB5R3 in mouse arterial ECs and show that α-globin can be reduced by either of two independent redox systems, CyB5R3/CyB5a and eNOS. Together, our findings provide new insights into the regulation of blood vessel contractility.