Ph.D Thesis

Ph.D StudentBlum Shany
SubjectHaptoglobin Genotype and Myocardial Infarction in Mice
DepartmentDepartment of Medicine
Supervisors PROF. Andrew Peter Levy
Full Thesis textFull thesis text - English Version


Background.    The haptoglobin (Hp) gene is polymorphic with two common classes of alleles denoted 1 and 2.  The Hp 2 allele protein is an inferior antioxidant compared to the Hp 1 allele protein. We have demonstrated in multiple longitudinal studies

involving over 30,000 participants that diabetic individuals with the Hp 2-2 genotype, 35% of all diabetic individuals, have as

much as a 500% increased risk of developing cardiovascular disease compared to Hp 2-1 and Hp 1-1 diabetic individuals.

The Hp 2 allele has also been found to be associated with increased myocardial infarction (MI) size in individuals with diabetes mellitus (DM).   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). 

We sought to understand the importance of oxidative stress in explaining why the Hp genotype determines MI size in DM.

Methods.    MI 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. An antioxidant drug (a synthetic mimic of glutathione peroxidase called BXT-51072) was given to the mice prior to the IR procedure by gastric lavage in order to affect infarct size.  

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 lipid peroxidation products of arachidonic acid  (hydroxyl-eicosatetraenoic acids-HETEs) in the myocardium. Redox active iron was greater in Hp 2 mice (0.45±0.11 uM vs. 0.14uM±0.05 uM, p=0.02) while 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 over 80% (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. Antioxidant treatment has been shown to decrease infarct size in these mice. We suggest that strategies designed to decrease oxidative stress in the subgroup of diabetic patients who carry the Hp 2-2 genotype may provide significant clinical benefit.