Abstract
Cell-free hemoglobin (Hb) resulting from hemolysis is redox-active. It disrupts the oxidoreducing microenvironment, shifting the balance unfavorably towards tissue cytotoxicity. Thus, immediate suppression of the Hb-redox activity and removal of the cell-free plasma Hb is vital for maintaining homeostasis and survival. Among several known Hb-binding plasma proteins, haptoglobin (Hp) is the primary antioxidant of Hb. However, Hb-mediated oxidative stress persists in the covalently bound Hb-Hp aggregates or when Hp is depleted during a severe hemolysis. We therefore inquired whether there is an alternative anti-oxidative defense tactic in the blood. Here, we identified an Hb-interactome in the plasma, constituting Hb, Hp and lipid-free apolipoprotein A-I (apoAI). We found that apoAI acts rapidly as a secondary antioxidant to interact with Hb and quench the Hb-redox activity. We showed that apoAI either acts independently or collaborates with Hp to downregulate Hb-redox activity. Following the association between apoAI and Hb, the apoAI facilitates the uptake of Hb by interacting with a scavenger receptor class B type 1 (SR-BI) displayed on macrophages and hepatocytes. Our findings suggest that apoAI mediates an efficient pathway for the elimination of cytotoxic Hb redox activity.