Haptoglobin Genotype Determines Myocardial Infarct Size in Diabetic Mice

ObjectivesWe sought to understand the importance of oxidative stress in explaining why the haptoglobin (Hp) genotype determines myocardial infarction (MI) size in diabetes mellitus (DM).BackgroundTwo common alleles (1 and 2) exist at the Hp locus in humans. The Hp 2 allele is associated with increased MI size in individuals with DM. In vitro, the Hp 2 protein is associated with increased generation of oxidatively active iron, whereas the Hp 1 protein is associated with increased production of the antioxidant cytokine interleukin (IL)-10.MethodsMyocardial infarction was produced by myocardial ischemia-reperfusion (IR) in DM C57BL/6 mice carrying the Hp 1 or Hp 2 allele. Myocardial oxidative stress after IR was assessed using electrospray ionization mass spectrometry. Redox active iron and IL-10 were measured in the serum after IR.ResultsMyocardial infarction size was significantly larger in Hp 2 mice as compared with Hp 1 mice (44.3 ± 9.3% vs. 21.0 ± 4.0%, p = 0.03), and these larger infarctions were associated with a significant increase in a panel of hydroxyl-eicosatetraenoic acids. Redox active iron was greater in Hp 2 mice (0.45 ± 0.11 μmol/l vs. 0.14 ± 0.05 μmol/l, p = 0.02), whereas IL-10 was greater in Hp 1 mice (85.8 ± 12.9 pg/μl vs. 46.7 ± 10.8 pg/μl, p = 0.04) after IR. Administration of an antioxidant (BXT-51072) to Hp 2 mice reduced myocardial injury after IR by more than 80% (p = 0.003), but no myocardial protection was provided by the antioxidant to Hp 1 mice.ConclusionsThe increased MI size in DM Hp 2 mice occurring after IR may be due to increased oxidative stress.