Abstract 1728: The Defect in HDL Function and Reverse Cholesterol Transport Found in Diabetic Mice with the Haptoglobin 2–2 Genotype Can Be Corrected with High Dose Antioxidant Therapy
Background. The primary function of the haptoglobin (Hp) protein is to clear free hemoglobin (Hb). Two common alleles exist at the Hp locus (1 and 2). We recently demonstrated that reverse cholesterol transport is impaired in individuals with Diabetes Mellitus (DM) and the Hp 2–2 genotype which may explain the increased incidence of cardiovascular disease in this population. We sought to
test the hypothesis that clearance of the Hp 2-Hb complex is slower in DM allowing more complex to bind to HDL thereby resulting in increased oxidative modification of HDL and inhibition of reverse cholesterol transport and
determine if antioxidant therapy could restore normal HDL function in Hp 2–2 DM mice.
Methods and Results. Injection of 125I-labeled Hp 1 or Hp 2-Hb complexes into non-DM mice demonstrated that the half-life of the Hp 2-Hb complex was 2–3 fold longer than the Hp 1-Hb complex (57.8 ± 2.8 vs. 20.4 ± 1.7 min). Moreover, in DM the half-life of the Hp 2-Hb complex was doubled while the half-life of the Hp 1-Hb complex was unchanged (103 ± 3.9 vs. 18.6 ± 1.8 min). Coimmunoprecipitation studies demonstrated that over 25% of the injected Hp 2-Hb complex was associated with HDL in DM mice representing a greater than 10 fold increase compared to Hp 1-Hb complex in non-DM mice. Coimmunoprecipitation studies in Hp 0 (knockout) mice demonstrated that the Hp protein was absolutely necessary for the interaction of Hb with HDL. Reverse cholesterol transport was impaired by DM in Hp 2 mice but this impairment was prevented by high dose antioxidant supplementation to these mice.
Conclusions. These data may explain why the Hp 2 genotype promotes less efficient reverse cholesterol transport in DM and suggests that strategies targeted to decrease oxidation of HDL by the Hp 2-Hb complex may improve HDL function.