The mechanisms of action of alpha- and beta-isoforms of antithrombin.
Antithrombin (AT) is the most important physiological inhibitor of thrombin. This effect can be increased more than a 1000-fold by heparin and heparin-like glycosaminoglycans, which induce a conformational change in the molecule. Two isoforms of AT exist in plasma: alpha and beta. The beta-isoform lacks one of four carbohydrate side-chains that are present on the alpha-isoform. The beta-isoform, which constitutes approximately 10% of plasma AT, has a higher affinity for heparin and heparin-like glycosaminoglycans than the alpha-isoform. In contrast to their distribution in plasma, the two isoforms of AT appear to be present in the same proportions in the vessel wall. After balloon injury of rabbit aorta, thrombin can be detected in the vessel wall, an effect that is inhibited by treatment with AT. The inhibitory effect of AT on thrombin coagulant activity in the injured vessel wall is attributable to the beta-isoform. The appearance of thrombin in the injured vessel wall can also be inhibited by heparin treatment, but this requires heparin to be circulating in plasma at the time of excision of the injured vessel wall. Thrombin has been suggested as a mitogen for smooth muscle cells. This effect of thrombin can be inhibited by AT, an inhibition that is increased by heparin in a concentration-dependent manner. The alpha-isoform of AT has a lower inhibitory capacity for the thrombin-induced proliferation of smooth muscle cells in the absence of heparin, compared with the beta-isoform, which is an effective inhibitor alone. This indicates that the beta-isoform of AT may use glycosaminoglycans produced by smooth muscle cells as a cofactor. In conclusion, the beta-isoform of AT appears to be an effective inhibitor of the thrombin coagulant activity induced by vessel wall injury. It is also a more effective inhibitor of the thrombin-induced proliferation of smooth muscle cells than the alpha-isoform.
Swedenborg
J
J
Department of Surgery, Karolinska Hospital, Stockholm, Sweden. kjsg@kir.ks.se
D000818:Animals; D000991:Antithrombins / Q000737:chemistry* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D006493:Heparin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D011487:Protein Conformation; D020033:Protein Isoforms / Q000097:blood / Q000737:chemistry; D011817:Rabbits; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000991:Antithrombins; D020033:Protein Isoforms; D006493:Heparin; D013917:Thrombin