Atherosclerosis is the underlying process leading to the occurrence of cardiovascular diseases that accounts for one-third the world’s mortality. Although multifactorial the pathogenesis of atherosclerosis is triggered to a large extent by elevated plasma cholesterol levels, and by the oxidation of low density lipoprotein (LDL). The central hypothesis of this proposal is that proteins containing Fe protoporphyrin IX (heme) or free heme itself might act as central mechanism via which LDL is oxidized as to become atherogenic.The vast majority of heme is inside red blood cells (RBC) as the prosthetic group of hemoglobin (Hb). Under homeostasis a small percentage of RBCs lyses intravascularly, resulting presence of cell-free Hb in plasma. Several defence mechanisms evolved to cope with the deleterious effects of cell-free Hb, as well as those of heme itself. Plasma cell-free Hb is bound by haptoglobin (Hp), whereas heme binds to hemopexin (Hx). The formed Hb-Hp and Hb-Hx complexes are cleared from circulation by hemophagocytic macrophages and the heme is degraded by heme-oxygenase-1 (HO-1). This control mechanism prevents the accumulation of cell-free Hb or free heme in plasma while allowing iron recycling. The impairment of this control mechanism leads to severe oxidative stress-mediated pathologies, e.g. Hp-/- as well as Hx-/- mice develop severe renal damage in response to hemolysis, suggesting that this mechanism plays a central role in preventing the pro-oxidant effects of cell-free Hb or heme.Previous work from the applicant and others have demonstrated that LDL can bind free heme with high affinity with kinetics that are faster than those of Hx and can cause LDL oxidation. It is likely therefore that under conditions in which the plasma concentration of LDL and/or cell-free Hb or heme levels become elevated, the production of heme-LDL complexes would be more prevalent contributing in a critical manner to the development of atherosclerosis.