Evolution Haptoglobins as Protein Drugs for Coronary Artery Diseas

Coronary Artery Disease (CAD) is the leading mortality over the world and second mortality of Taiwan. CAD is a chronic inflammation and ischemic heart disease. Currently, treatments of coronary artery disease are limited in controlling symptoms and slowing or stopping the progression of disease. The overall goal for this program project is to develop haptoglobin (Hp) protein drug drugs for therapeutic application of CAD. Dysfunction of the endothelial cells in blood vessels is one of the major events in the development of atherosclerosis. Inflammation involve in the initiative of atherosclerotic lesion process. In the progression, monocytes recruitment contributes to the early stage of atherosclerosis. Oxidation stress is another remarkable proinflammatory factor will induce endothelial cell inflammation and stimulate monocytes recruitment and differentiated to resident macrophage in vascular wall. Similar to blood types, there is a specific Hp phenotype 1-1, 2-1, or 2-2 for each individual attributed by two common alleles (Hp1 and Hp2). Hp1-1, a homozygous form occurs as a dimer; Hp2-2, a homozygous form gives a series of circle polymers; and the heterozygous Hp2-1 form with a different series of linear polymers. We found that different phenotype individual had different susceptible for atherosclerosis. Our preliminary data showed that Hp have strong anti-oxidant activity and decrease the differentiated adhesive monocytes amount in vitro. Furthermore, Hp exist strong enhance ability for human umbilical vein endothelial cells (HUVECs) proliferation, migration, and angiogenesis in vitro. Angiogenesis activity enhance in capillary formation will increase blood and nutrient supplement in atherosclerotic lesion area. According, Angiogenetic function will be benefit for the therapeutic application of coronary artery disease. The activities can accelerate wound healing process in the oxidative and inflammation initiated atherosclerotic lesion and improve cardiomyocyte function in coronary artery damaged lesion. The specific aims are: 1. To investigate the therapeutic efficiency of Hp in cell level and estimate the molecular and signal transduction regulation mechanism. 2. To evaluate the formula of Hp loaded fucoidan-based nanoparticles as inflammation targeting nanoparticle and utilization of pharmaceutical treatments. 3. To develop Hp coated stent and to evaluate the benefits of coated stent for coronary artery disease and restenosis prevention in animal model. 4. To validate the pharmaceutical market potential of the developed Hp protein drugs and Hp embed inflammation targeting nanoparticle for coronary artery disease treatment and restenosis prevention. Expectation this study could contribute to coronary artery disease therapy.