Hemoglobin redox reactions and red blood cell aging

Abstract

Significance: The physiological mechanism(s) for recognition and removal of red blood cells (RBCs) from circulation after 120 days of its lifespan is not fully understood. Many of the processes thought to be associated with the removal of RBCs involve oxidative stress. We have focused on hemoglobin (Hb) redox reactions, which is the major source of RBC oxidative stress.

Recent advances: The importance of Hb redox reactions have been shown to originate in large parts from the continuous slow autoxidation of Hb producing superoxide and its dramatic increase under hypoxic conditions. In addition, oxidative stress has been shown to be associated with redox reactions that originate from Hb reactions with nitrite and nitric oxide (NO) and the resultant formation of highly toxic peroxynitrite when NO reacts with superoxide released during Hb autoxidation.

Critical issues: The interaction of Hb, particularly under hypoxic conditions with band 3 of the RBC membrane is critical for the generating the RBC membrane changes that trigger the removal of cells from circulation. These changes include exposure of antigenic sites, increased calcium leakage into the RBC, and the resultant leakage of potassium out of the RBC causing cell shrinkage and impaired deformability.

Future directions: The need to understand the oxidative damage to specific membrane proteins that result from redox reactions occurring when Hb is bound to the membrane. Proteomic studies that can pinpoint the specific proteins damaged under different conditions will help elucidate the cellular aging processes that result in cells being removed from circulation.

FIG. 1.

Red cell oxidative stress. Scheme showing how both endogenous hemoglobinautoxidation and exogenous oxidants generate oxidative stress that can result in cellular aging and functional impairment. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.

FIG. 2.

Leakage of calcium into red blood cells (RBCs). Calcium induced reactions in the RBC that contribute to cell shrinkage. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.

FIG. 3.

Redox reactions associated with increased autoxidation of partially oxygenated hemoglobin (Hb) bound to the red cell membrane. The formation of superoxide and hydrogen peroxide result in formation of hemichromes and degradation of the heme releasing free iron and fluorescent degradation products that interact with the membrane. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.

FIG. 4.

Red cell reactions involving nitric oxide (NO) released from the endothelium. NO can be oxidized to form nitrite that is taken up by the cell and reduced back to NO by deoxygenated Hb chains. NO can also react with superoxide in the cell and in the plasma to produce peroxynitrite, which is a highly toxic compound that reacts with Hb. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars.