Genetically Determined Heterogeneity in Hemoglobin Scavenging and Susceptibility to Diabetic Cardiovascular Disease

Abstract

Abstract-A major function of haptoglobin (Hp) is to bind hemoglobin (Hb) to form a stable Hp-Hb complex and thereby prevent Hb-induced oxidative tissue damage. Clearance of the Hp-Hb complex can be mediated by the monocyte/macrophage scavenger receptor CD163. We recently demonstrated that diabetic individuals homozygous for the Hp 2 allele (Hp 2-2) were at 500% greater risk of cardiovascular disease (CVD) compared with diabetic individuals homozygous for the Hp 1 allele (Hp 1-1). No differences in risk by Hp type were seen in individuals without diabetes. To understand the relationship between the Hp polymorphism and diabetic CVD, we sought to identify differences in antioxidant and scavenging functions between the Hp types and to determine how these functions were modified in diabetes. The scavenging function of Hp was assessed using rhodamine-tagged and 125 I-Hp in cell lines stably transfected with CD163 and in macrophages expressing endogenous CD163. We found that the rate of clearance of Hp 1-1-Hb by CD163 is markedly greater than that of Hp 2-2-Hb. Diabetes is associated with an increase in the nonenzymatic glycosylation of serum proteins, including Hb. The antioxidant function of Hp was assessed with glycosylated and nonglycosylated Hb. We identified a severe impairment in the ability of Hp to prevent oxidation mediated by glycosylated Hb. We propose that the specific interaction between diabetes, CVD, and Hp genotype is the result of the heightened urgency of rapidly clearing glycosylated Hb-Hp complexes from the subendothelial space before they can oxidatively modify low-density lipoprotein to atherogenic oxidized low-density lipoprotein.

Haptoglobin Polymorphism and Association with Complications in Ghanaian Type 2 Diabetic Patients

“…Diabetic complications were strongly associated with Hp 2-2 and Hp 2-1, Hp 1-1, Hp 2-1 M, in a decreasing order in this study. The reasons for this could be due to (i) differences in Hb binding capacities of the different Hp phenotypes [47]; (ii) the shape and size of the Hp phenotypes [17]; (iii) an increase in redox active iron in the plasma of humans with the Hp 2-2 phenotype [48]; (iv) the ''clearance'' of Hp-Hb complex in the blood circulation after intravascular haemolysis by CD163 which is less effective in Hp 2-2 individuals [23]; and (v) the better antioxidant effects of Hp 1-1 phenotypes on low-density lipoprotein (LDL) oxidation than Hp 2-2 [49,50]. These may explain the susceptibility of Hp 2-2 individuals to complications such as coronary artery diseases (CAD), neuropathy, nephropathy and hypertension.…”

“…The generation of this oxidative stress [22] may be moderated by exogenous and host genetic factors that scavenge free radicals. Endogenous antioxidants such as glutathione and certain haptoglobin (Hp) phenotypes are important in the prevention and protection of blood vessel walls of internal organs against oxidative stress which is normally increased in the diabetic state by the presence of glycated haemoglobin [23].…”

Pharmacogenomic effect of vitamin E on kidney structure and function in transgenic mice with the haptoglobin 2-2 genotype and diabetes mellitus

“…The fundamental mechanism explaining why Hp 2-2 DM mice have more renal damage compared with Hp 1-1 DM mice can be explained by differences in the manner in which the two Hp types regulate the disposition of extracorpuscular hemoglobin and more specifically hemoglobin-derived iron (1,2,29). Extracorpuscular hemoglobin is increased in diabetes due to increased red cell fragility resulting in a shorter red blood cell half time (46).…”

“…Furthermore, the rate of clearance of hemoglobin is Hp type dependent. Hp 1-1 directs a more rapid clearance of free hemoglobin via uptake by the CD163 macrophage scavenger receptor (1). In the diabetic state, this is particularly important as the ability of Hp to block the oxidative activity of hemoglobin is impaired when hemoglobin becomes glycated (2).…”

“…The structure and function of the two Hp allele protein products are distinct. We and others showed in vitro and in vivo that the Hp 1 protein is a superior antioxidant to the Hp 2 protein (1,2,29).…”