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. Author manuscript; available in PMC: 2014 Feb 19.
Published in final edited form as: J Am Coll Cardiol. 2013 Jan 9;61(7):728–737. doi: 10.1016/j.jacc.2012.09.063

Figure 3. Proposed Biological Mechanism to Explain Increased Risk of CHD in Hyperglycemic Individuals With the Hp2-2 Genotype.

Figure 3

Hemoglobin (Hb) released intravascularly from erythrocytes (red blood cells [RBC]) is rapidly bound by haptoglobin (Hp) protein to form an Hp–Hb complex that is cleared by scavenger receptor CD163. However, this clearance by CD163 is impaired in Hp2 as well as under hyperglycemic conditions in vivo, resulting in increased amounts of circulating Hp2:Hb complex in Hp2-2 individuals with hyperglycemia. Moreover, we have shown that glycosylation of Hb impairs the ability of the Hp2-2 protein to act as an antioxidant, thus resulting in increased oxidative activity of the glycosylated Hp2:Hb complex. This pro-oxidant Hp2:Hb complex can bind to high-density lipoprotein (HDL) and produce reactive oxygen species that oxidize cholesterol and its related components such as apolipoprotein A (ApoA1), glutathione peroxidase (GPx), and lecithin-cholesterol acyltransferase (LCAT), thereby decreasing the function of HDL as both an antioxidant and in reverse cholesterol transport. The Hp2-1 protein is a linear polymer, intermediate in size and antioxidant capacity (2). CHD = coronary heart disease. Adapted from Asleh et al. (27).