M.Sc Thesis

M.Sc StudentFahoum Lana
SubjectDiabetic Angiogenesis and Haptoglobin Genotype
DepartmentDepartment of Medicine
Supervisor PROF. Andrew Peter Levy
Full Thesis textFull thesis text - English Version


There are three phenotypes of Haptoglobin (Hp), denoted Hp1-1, Hp2-1 and Hp2-2.The major function of Hp is to bind to hemoglobin and thereby prevent hemoglobin-induced oxidative tissue damage.We have recently demonstrated in multiple independent population-based longitudinal and cross sectional analyses that Hp polymorphism is predictive of the risk for numerous diabetic complications.Specifically, Hp1-1 confers significant protection from diabetic retinopathy, diabetic nephropathy, and coronary artery disease (CAD). Hp2-1 confers a partial protection, and Hp2-2 can be regarded as a risk factor for diabetes-related vascular disorders. Pathological angiogenesis plays a major role in many diseases such as cancer, atherosclerosis, CAD, cardiac failure, and diabetic retinopathy.In this work, we hypothesize that the Hp polymorphism is important in determining the level of angiogenesis in the diabetic setting, thus playing a central role in the development of diabetic vascular complications such as, diabetic retinopathy and nephropathy and CAD progression. We aimed to determine the extent of the difference in angiogenic activity between the Hp phenotypes in an in vitro setting and to identify important factors meditating this angiogenic activity. Last we aimed to establish the contribution of the angiogenic activity of the different Hp phenotypes in a diabetic setting in vitro.We tested our hypothesis using several complementary approaches in vitro.Our results indicate a proliferative effect of the Hp phenotypes dependent on concentration. Hp1-1 demonstrated more prominent angiogenic characteristics such as having a proliferative effect on THP-1 cells and HUVEC and inducing the release of pro-angiogenic factors IL-6 and IL-10. On the other hand, Hp 2-2 presented a more prominent anti-angiogenic effect at higher concentrations such as inhibiting spontaneous proliferation of THP-1 cells and HUVEC.We suggest two possible mechanisms, connecting the different angiogenic function of the Hp phenotypes to the finding that Hp polymorphism is predictive of the risk for numerous diabetic vascular complications.The first one suggests an angiogenic activity of Hp dependent on concentration. Thus conferring both angiogenic and anti-angiogenic properties in the same individual depending on the concentration of Hp in the microcirculation.The second possible mechanism suggests Hp angiogenic properties are not dependent on concentration, rather than attributed to other functions of Hp such as its anti-oxidant properties.Taken together, our findings may have implications in understanding inter-individual differences and in developing a model to test different therapeutic agents to reduce mortality and morbidity from diabetic vascular complications attributed to the Hp polymorphism.