Abstract 601: Haptoglobin Genotype Determines Myocardial Infarct Size in Diabetic Mice

Abstract

Objectives. We sought to understand the importance of oxidative stress in explaining why the haptoglobin (Hp) genotype determines myocardial infarction (MI) size in diabetes mellitus (DM). Background. Two common alleles (1 and 2) exist at the Hp locus in man. The haptoglobin (Hp) 2 allele is associated with increased MI size in individuals with DM. Enhanced oxidative stress resulting in increased production of reactive oxygen species has been shown to play a critical role in the generation of myocardial ischemia-reperfusion injury (IR). Redox active labile plasma iron (LPI) and the anti-inflammatory cytokine interleukin-10 (Il-10) are known to play major roles in determining the extent of myocardial injury after myocardial IR. In vitro the Hp 2 protein is associated with increased generation of oxidatively active iron while the Hp 1 protein is associated with increased production of the antioxidant cytokine interleukin-10 (Il-10). Methods. MI was produced by myocardial ischemia-reperfusion (IR) using an occlusion of the left anterior descending artery followed by reperfusion 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. Results. MI size was significantly larger in Hp 2 mice as compared to 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 (HETEs). Redox active iron was greater in Hp 2 mice (0.45±0.11uM vs. 0.14uM±0.05uM, p=0.02) while Il-10 was greater in Hp 1 mice (4170±646 pg/ml vs. 2115±541 pg/ml, p=0.03) after IR. Administration of an antioxidant (glutathione peroxidase mimic BXT-51072) to Hp 2 mice reduced myocardial injury after IR by over 80% (44.3±9.3 % vs. 7.0±3.1%, p=0.003). but no myocardial protection was provided by the antioxidant to Hp 1 mice. Conclusions. The increased MI size in DM Hp 2 mice occurring after IR may be due to increased oxidative stress. We suggest that strategies which will be designed to decrease this oxidative stress may provide significant myocardial protection.