Antithrombin III inhibits thrombin-induced proliferation in human arterial smooth muscle cells.

Abstract

Thrombin has attracted increasing attention as a possible mitogen for vascular smooth muscle cells in lesion development both after vascular injury and in atherogenesis. In this study, the ability of antithrombin III to inhibit a-thrombin-induced DNA synthesis and cell proliferation in human arterial smooth muscle cells was analyzed. We demonstrate a concentration-dependent initiation of DNA synthesis and cell proliferation by a-thrombin. This effect was abolished when complex formation with antithrombin HI was allowed before thrombin was added to the cell cultures. Addition of a-thrombin and antithrombin III simultaneously at the beginning of the incubation period also resulted in an inhibition of thrombin-induced DNA synthesis, but to a lower degree. The inhibitory activity of antithrombin III was enhanced in the presence of heparin, which on its own had no inhibitory effect on thrombin-induced DNA synthesis. In contrast, the mitogenic activity of a-thrombin could be inhibited by heparin in the presence of low concentrations of serum. This inhibition was dependent on the presence of antithrombin III in serum, since heparin lacked effect if antithrombin III was depleted from serum by immunoaffinity chromatography. Analysis of the enzymatic activity of thrombin showed that the influence on catalytic activity of thrombin corresponded to the mitogenic activity of thrombin in the presence of heparin, antithrombin III, and serum. The results suggest that the mitogenic activity of thrombin is regulated by antithrombin III. Therefore, antithrombin III may serve dual functions by inhibiting thrombin in the coagulation cascade and by neutralizing its growthpromoting effects on vascular smooth muscle cells. (Arterioscler Thromb. 1994;14:254-260.)

Thrombin receptor activation elicits rapid protein tyrosine phosphorylation and stimulation of the raf-1/MAP kinase pathway preceding delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for an obligate autocrine mechanism promoting cell proliferation induced by G-protein-coupled receptor agonist.

“…These data are in agreement with previous studies using both rat (9) and human arterial smooth muscle cell lines (34,46). Furthermore, the delayed mitogenic responses of RASM cells after thrombin receptor activation are similar to our previous studies on angiotensin II and endothelin-1, two other potent vasoactive agonists that bind to distinct G protein-coupled receptors (36,38).…”

The effect of dietary arachidonic acid on platelet function, platelet fatty acid composition, and blood coagulation in humans

“…Thus, there may be no physiological significance to this difference, particularly considering that the antithrombin-III levels were unaffected by the high-AA diet. Antithrombin-III is considered a measure of the tendency for the blood to undergo thrombosis in vivo and has been correlated with increased incident of myocardial infraction in humans (31)(32)(33)(34).…”

Thrombomodulin Activity of Fat-Derived Microvascular Endothelial Cells Seeded on Expanded Polytetrafluorethylene

“…It has been generally accepted that this is a consequence of platelet adhesion and activation of the coagulation cascade on the graft [3, 4]. Thrombosis on the graft surface has also been linked to the development of myointimal hyperplasia [5, 6, 7]. As venous material for arterial reconstructions is often not available, the use of prosthetic small-diameter vascular grafts with known inferior patency rates is unavoidable.…”