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Cardiovascular Biology Research Program

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OMRF scientists discover promising new path for treating traumas

OMRF drug wins national award

Charles T. Esmon, Ph.D. Member, Cardiovascular Biology Research Program Lloyd Noble Chair in Cardiovascular Biology Member, National Academy of Sciences Investigator, Howard Hughes Medical Institute Adjunct Professor, Departments of Biochemistry & Molecular Biology and   Pathology, University of Oklahoma Health Sciences Center

In my lab, we study the mechanisms that control the process of blood clotting and the links between the controls of blood clotting and inflammation.

Blood clots are the cause of many serious human diseases, including heart attacks, strokes, pulmonary emboli, and venous thrombosis (phlebitis). They contribute to the mortality and morbidity of septic shock, acute trauma injury, and some of the complications of diabetes.

To understand why abnormal clots occur, we examine the mechanisms by which the normal blood-clotting system is regulated and compare the regulation under normal circumstances to the pathogenic circumstance. To accomplish this, we seek to (1) identify new factors that are involved in regulating the blood-clotting process, (2) understand how the proteins function in the control of the process, (3) understand how the genes are regulated, (4) examine the influence of defects in the function of the proteins on the human disease process, (5) examine the influence of inhibition of the function of the proteins in animal models of human disease, (6) use crystallographic and biophysical techniques to determine the molecular structure of the proteins and complexes, and (7) determine how the regulatory proteins of the coagulation system control inflammation, and vice versa.

Work from our laboratory and from many others has shown that hereditary tendencies toward developing venous thrombosis are most commonly the result of defects in the proteins that participate in the protein C anticoagulant pathway. These proteins are also involved in protection from the deleterious effects of bacterial infection (a process leading to septic shock) of the bloodstream, where the engagement of the protein C anticoagulant pathway is critical to the survival of the patients. Ongoing studies are aimed at elucidating how the pathway protects the individual from septic shock. Earlier we demonstrated that activated protein C (APC) could protect animals, including nonhuman primates, from the lethal effects of Escherichia coli infusion. APC was shown to block coagulation induced by E. coli infusion, facilitate clot lysis, and limit cytokine elaboration. As such, it was uniquely poised to serve as a candidate for the treatment of severe sepsis in humans, a disease that has a mortality rate of approximately 30-50 percent. A recent phase III trial conducted by Eli Lilly confirmed this hypothesis and demonstrated a decrease of approximately 20 percent in the death rate of severe sepsis patients given APC (this drug is now called Xigris). These clinical results provide impetus to establish the multiple modes of action by which APC accomplishes this function. My laboratory is currently studying the multiple modes of action that make APC effective as a therapy for inflammatory diseases like sepsis. Greater understanding of these mechanisms is likely to generate new diagnostic and therapeutic approaches.

The newest member of the protein C pathway, the endothelial protein C receptor (EPCR), was identified in our laboratory, but the influence of the receptor on the shock process was unknown. Blocking the ability of the receptor to function results in dramatically increased sensitivity to bacterial infusion, resulting in increased blood clotting, increased inflammation, and vascular degeneration. At least part of this function is manifested because of an unexpectedly strong contribution of EPCR to protein C activation. We have now deleted the EPCR gene in mice and have shown that this deletion leads to a hypercoaguable phenotype that is also highly sensitized to death from septic shock. In the deficient mice, inflammation and loss of vascular integrity play dominant roles in their hypersensitivity to inflammatory challenges.

EPCR has an additional unusual property: it can traffic from the plasma membrane and carry APC as cargo. This trafficking appears to alter the expression of a subset of genes. These properties suggested that EPCR plays a critical role in development. This was borne out when deletion of the gene in mice caused an early embryonic lethal phenotype (about embryonic day 8.5). Replacement of wild-type EPCR in mice with specific mutations designed to block single EPCR functions is in progress to elucidate the physiological significance of each of the functions described above.

A complete understanding of how the blood-clotting process is regulated requires an appreciation of the structure of the proteins involved in the process, both alone and in the complexes responsible for their biological activity. Our group solved the crystal structure of EPCR bound to a portion of protein C. The structure confirmed the prediction from the primary sequence that EPCR is structurally very similar to the major histocompatibility complex class I family of molecules. Binding to protein C, however, involves a region of EPCR distinct from the antigen-binding groove found in the class I proteins. A tightly bound lipid (primarily phosphatidylcholine) is, however, present in this groove. Current studies indicate that EPCR deficient mice develop anti-phospholipid antibodies and that these antibodies have significant inhibitory effects on the activated protein C anticoagulant properties. The latter finding probably contributes to the propensity of patients with these antibodies to develop arterial, venous and microvascular blood clots.

When blood vessels are injured, as occurs in angioplasty, the vascular response for the vessel wall is for the cells to proliferate (restenosis). The resultant narrowing of the blood vessel contributes to the requirement to repeat the procedure. In mice, they have found that modulation of the protein C pathway can decrease this vascular thickening dramatically. These results suggest a new approach to treating a common clinical problem.

Together, these studies should improve our understanding of the blood-clotting process in health and disease.