Abstract 3517: Clearance Of The Haptoglobin 2–2-Hemoglobin Complex Is Impaired In Diabetes Mellitus Resulting In A Modification Of HDL Structure And Defective Reverse Cholesterol Transport
Background: Haptoglobin (Hp) plays a key role in hastening the clearance of extracorpuscular 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.
Methods and Results: Injection of I125- 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 ± 6.2 vs. 20.4 ± 3.8 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 ± 9.5 vs. 18.6 ± 4.5 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. Reverse cholesterol transport was significantly impaired by DM in Hp 2 mice but this impairment was prevented by vitamin E treatment in 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.