Evaluation of Haptoglobin and Its Subunits as Protein Drugs for Ischemic Heart Diseases

Hp is known as an acute phase protein, one key physiologic function of human plasma Hp is to capture the free hemoglobin in plasma allowing hepatic clearance of hemoglobin and preventing the hemoglobin induced oxidative damage in tissues. Hp also acts as an antibacterial agent playing a role in depletion iron required for growth in an acute phase response. Most recently, we have shown that cells transfected with Hp cDNA attenuate the hydrogen peroxide challenged damage, suggesting that Hp is an extremely potent antioxidant. 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. More recently, several functional differences between Hp phenotypes have been demonstrated that appear to have important biological and clinical consequences. Our published articles and preliminary data showed that Hp and its subunits several functional activities associated with ischemic heart diseases prevention. First, Hp and subunits (alpha-1, alpha-2, and beta-chain) were potent for anti-oxidant activity more efficiency than the anti-oxidant drug, probucol. They could inhibit LDL oxidation to prevent atherosclerosis. Second, Hp and subunits could inhibit PMA- and Hb-induced inflammation response. Inhibition of MCP-1 and ICAM-1/VCAM-1 express in cultured HUVECs. Third, Hp and its subunits were potent of angiogenesis enhance factors. Enhance in endothelial proliferation will accelerate wound repair to decrease restenosis after angiographic therapy. Enhance in capillary formation will increase blood and nutrient supplement. Angiogenesis will be benefit for ischemic heart diseases. The major goal in this project is to evaluation of haptoglobin and its subunits as protein drugs for ischemic heart diseases. In addition, one of the raising technologies, nanocapsule formulation has attracted much interest in the pharmaceutical industry due to the capability to improve pharmacokinetic characteristics of the carried drugs, the solubility, bioavailability, and the possibility intelligent release control. In this project, our group will develop the nanocapsule to delivery protein drugs for ischemic heart diseases. The specific aims are: 1. to investigate the therapeutic efficiency of Hp and its subunits treatment, for molecular and signal transduction regulation in cell level. 2. To evaluate the effect of nanocapsule embed Hp or its subunits and utilization of pharmaceutical treatments. 3. To develop Hp or its subunits coated stent and to evaluate the benefits of coated stent for ischemic heart disease and restenosis prevention in animal model. 4. To validate the pharmaceutical market potential of the developed Hp (and its subunits) drugs and Hp coated stents for ischemic heart diseases treatment and restenosis prevention. Expectation this study could contribute to ischemic heart diseases therapy.