Heparin from porcine or bovine tissues is used to treat diseases such as venous thrombosis, pulmonary embolism, and coronary artery thrombosis. The anticoagulant effects of heparin result from binding to antithrombin and heparin cofactor II (HCII), which are thereby activated to inhibit thrombin and other coagulation enzymes. Dermatan sulfate is a related polymer that specifically activates HCII. Dermatan sulfates and heparin isolated from the marine invertebrates Styela plicata and Ascidia nigra differ from mammalian glycosaminoglycans in the degree and position of sulfation. These differences have profound effects on their anticoagulant properties in vitro, including their ability to activate antithrombin and HCII. In the present study, ascidian glycosaminoglycans will be compared with their mammalian counterparts to determine the relative contributions of HCII and antithrombin to the antithrombotic activities of heparin and dermatan sulfate.
The specific aims are as follows: (1) Prepare low molecular weight derivatives of ascidian glycosaminoglycans, characterize their structures by nuclear magnetic resonance spectroscopy, and determine their anticoagulant activities in vitro. (2) Compare the anticoagulant properties of ascidian dermatan sulfate and heparin with their low molecular weight derivatives in vivo. (3) Investigate the antithrombotic activity of the ascidian glycosaminoglycans in experimental venous and arterial thrombosis models in rats and in normal or HCII-deficient mice. (4) Study the effects of the ascidian glycosaminoglycans and their low molecular weight derivatives on platelet function and determine the hemorrhagic effects of these polymers in vivo. These studies will provide insight into the antithrombotic mechanisms of glycosaminoglycans and may lead to development of anticoagulants with fewer side effects, improved pharmacokinetics, or greater potency than standard heparin preparations. This research will be done primarily in Brazil as an extension of NIH grant 5 R0l HL 55520-05.
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