Ph.D Thesis

Ph.D StudentAsaf Roy
SubjectHaptoglobin Genotype and Cardiac Remodeling after Myocardial
Ischemia in Mice
DepartmentDepartment of Medicine
Supervisor PROF. Andrew Peter Levy
Full Thesis textFull thesis text - English Version


Diabetes mellitus is characterized by increased cardiovascular morbidity and mortality. Conventional cardiovascular risk factors cannot fully explain the increased risk for cardiovascular complications in diabetes. Therefore, there is a growing interest in genetic factors that may be involved in the development of cardiovascular disease in diabetes. The haptoglobin gene is one such candidate gene.

Haptoglobin is an acute phase serum protein whose main known function is scavenging of free hemoglobin from the blood stream. In man, there exists a functional polymorphism in the gene for haptoglobin with two classes of alleles denoted Hp1 and Hp2 that result in three phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2) which differ in structure and function. In clinical studies summing thousands of patients we have shown that in the presence of diabetes, Hp 2-2 genotype is an independent risk factor for cardiovascular complications. Diabetic individuals that carry the Hp 2-2 genotype are at increased risk for myocardial infarction, stroke, and cardiovascular death. In particular, Hp 2-2 diabetic individuals have larger infarct size, and increased mortality rate and congestive heart failure after myocardial infarction. We sought to recapitulate these findings in transgenic mice.

In a transgenic mouse model of acute myocardial ischemia and reperfusion we have found larger infarct size in Hp 2-2 diabetic mice compared with Hp 1-1 diabetic mice. We measured a significant elevation in a panel of oxidation products only in hearts of Hp 2-2 diabetic mice that underwent myocardial infarction. Furthermore, we have shown that administration of a synthetic mimic of glutathione peroxidase to Hp 2-2 mice prior to myocardial infarction resulted in a significant reduction in infarct size in these mice.

In a mouse model of chronic myocardial ischemia we found that after 24 hours of complete occlusion of the left anterior descending artery infarct size was similar in Hp 1-1 and Hp 2-2 diabetic mice. However, mortality rate at 30 days was significantly higher in Hp 2-2 diabetic mice. In echo-cardiography we have shown that left ventricle dimensions in Hp 2-2 diabetic mice were significantly increased 30 days after myocardial infarction compared with Hp 1-1 diabetic mice. In addition, loss of left ventricle function was significantly higher in Hp 2-2 diabetic mice 4 days after myocardial infarction compared to Hp 1-1 diabetic mice.

Therefore, this mouse model may serve as a platform to further investigate the basic mechanisms underlying the differences in the outcomes after myocardial infarction between the Haptoglobin genotypes.