Cardiovascular disease is currently the leading cause of morbidity and mortality in developed countries. Chronic lesions of atherosclerosis form the base for the development of acute thrombi, which lead to heart attack and stroke. Currently available therapeutic maneuvers have their limitations. It is now known that atherosclerosis has an important inflammatory component. Interaction between Pselectin expressed on endothelial cells and platelets, and P-selectin glycoprotein ligand-1 (counter receptor) displayed on leukocytes, forms an important mechanism to recruit inflammatory cells to the vessel wall. Inhibition of this interaction helps to maintain vascular patency. CD39/NTPase-1 is a key enzyme expressed on endothelial cells and platelets, which inhibits platelet reactivity and maintains endothelial integrity and CD39-null mice display thrombotic sequelae. Transgenic mice over expressing human CD39 display prolonged bleeding times and protection from collagen-induced vein thrombosis. This proposal will characterize the usefulness of a novel therapeutic agent that will target the platelet inhibitory activity of soluble CD39 to the activated endothelial-platelet microenvironment by incorporation of a PSGL-1 tag (rSolPSGL-Cd39). It is designed to reduce inflammation and thrombus formation in the proximity of injured vessel wall. The novel therapeutic agent with antithrombotic and anti-inflammatory activities will be produced as a recombinant protein and its function will be characterized by in vitro tests of platelet aggregation, binding to activated platelet and endothelial cells, and in vivo testing such as tail bleeding time, and monitoring of pharmacokinetics. The potency of rSolPSGL-CD39 to maintain vascular patency, will be assessed in animal models of mechanical arterial injury and also deep vein thrombosis. The ability of CD39 expression to modify atherosclerosis, will be analyzed in the CD39 transgenic mice and CD39-null mice bred on a background of apolipoprotein E-null and low density lipoprotein receptor-null mice.
| Sashindranath, Maithili; Dwyer, Karen M; Dezfouli, Shala et al. (2017) Development of a novel strategy to target CD39 antithrombotic activity to the endothelial-platelet microenvironment in kidney ischemia-reperfusion injury. Purinergic Signal 13:259-265 |
