|Ph.D Student||Kalet-Litman Shiri|
|Subject||Elucidation of the Mechanisms Responsible for the|
Interaction between the Haptoglobin Polymorphism
and Diabetic Cardiovascular Disease in
an In-Vivo Model
|Department||Department of Medicine||Supervisor||Professor Andrew Peter Levy|
|Full Thesis text|
The major cause of acute coronary thrombosis is atherosclerotic plaque rupture and the precursor lesion has been termed the high risk plaque. Pathological features of high risk plaques include a large lipid necrotic core, thin fibrous cap, inflammatory infiltrate, and intraplaque hemorrhage (IPH). Extracorpuscular hemoglobin (Hb) released from red blood cells after IPH represents a potent stimulus for inflammation within the plaque. The main function of the Haptoglobin (Hp) protein is to bind extracorpuscular Hb and prevent it from mediating deleterious effects. The Hp protein is polymorphic with two common alleles denoted 1 and 2. We and others have demonstrated in multiple independent longitudinal and cross sectional studies that the Hp 2-2 genotype is associated with an increased risk for atherosclerotic CVD in individuals with Diabetes Mellitus (DM). The central goal of this work was to provide a basic understanding why there is an increased risk for atherosclerotic CVD in Hp 2-2 DM patients. This was achieved by developing a model of CVD in mice genetically modified at the Hp locus and by analyzing differences in atherosclerotic lesions in these mice. We hypothesized that there may be Hp-type dependent difference in Hb-mediated oxidative stress and macrophage-mediated inflammation within the atherosclerotic plaque. In this study we have provided direct evidence that the Hp genotype contributes to the modulation of the number of macrophages in the atherosclerotic plaque. We have suggested that this increase in macrophage accumulation in Hp 2-2 plaques may be secondary to elevated plaque oxidative stress due to increased intraplaque iron derived from Hb. This work has also sought to explain the recent observation made in our laboratory that there is a defect in HDL function in Hp 2-2 DM individuals and mice. We have provided evidence in this work for the association of Hp and Hb with HDL in Hp 2-2 diabetic individuals and mice and for a concurrent increase in the amount of lipid peroxidation in the HDL of Hp 2-2 diabetic individuals and mice. We have proposed that association of Hb with HDL results in the oxidative modification of HDL associated proteins and lipids and the loss of function of HDL may be the direct result of its oxidative modification. These results may explain the ability of antioxidants (vitamin E) to improve HDL function in Hp 2-2 individuals and mice.