Erythrocyte Lysis and Heme Release Probably via Binding to Hemoglobin

Heme is present in the hemoglobin in blood. Extracellular hemoglobin is easily oxidized and readily releases heme. Free heme can be quite cytotoxic, particularly in the presence of oxidants or activated phagocytes. Because of the hydrophobic nature of heme, it can rapidly intercalate with cell membranes and cause severe damage. Hemoglobin-derived heme has been demonstrated to act as a catalyst for the oxidation of lowdensity lipoprotein (LDL), which in turn causes atherosclerosis (Jeney et al., 2002). In the mid 1990s, Utans and coworkers and our team identifi ed a novel macrophage factor from different systems and named it allograft infl ammatory factor-1 (AIF-1) and daintain, respectively (Utans et al., 1995; Chen et al., 1994, 1997). When aligned, the amino acid sequences of daintain and AIF-1 are highly similar. Therefore, we call the polypeptide daintain/AIF-1. During the last 10 years, this peptide has rapidly gained interest by a fast growing group of scientists. To date, an overwhelming body of evidence indicates that endogenous daintain/AIF-1 and its related proteins (Deininger et al., 2002; Ohsawa et al., 1997) affect numerous critical cellular functions including the survival and pro-infl ammatory activity of macrophages (Watano et al., 2001), the augmentation of the production of cytokines in a mouse macrophage cell line (Yang et al., 2005), the promotion of vascular smooth muscle cell proliferation and migration, the association with neointimal hyperplasia and p38 kinase activity (Autieri et al., 2003; Sommerville et al., 2009; Chen et al., 2004), as well as the regulation of endothelial cell activation, signal transduction, and vasculogenesis (Ying et al., 2009). But the potential role of daintain/AIF-1 in blood and the mechanism by which it acts are not clear. Often it is possible to deduce the function of a protein by identifi cation of its binding partners. In the present study, we have used this approach to uncover the role of daintain/AIF-1 in blood and its mechanism of action.