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(Circulation. 1998;97:589-595.)
© 1998 American Heart Association, Inc.

Basic Science Reports

Thrombin-Induced Mitogenesis in Coronary Artery Smooth Muscle Cells Is Potentiated by Thromboxane A₂ and Involves Upregulation of Thromboxane Receptor mRNA

T.-Ph. Zucker, MD; D. Bönisch, BSc; S. Muck, BSc; A.-A. Weber, MD; E. Bretschneider, MD; E. Glusa, MD; ; K. Schrör, MD

From Institut für Pharmakologie (D.B., S.M., A.-A.W., K.S.) and Institut für Klinische Anaesthesiologie, Heinrich-Heine-Universität Düsseldorf (Germany) (T.-Ph.Z.); and Forschungszentrum für Vaskuläre Biologie und Medizin der Friedrich-Schiller-Universität Jena, Erfurt, Germany (E.B., E.G.).

Correspondence to Karsten Schrör, MD, Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Moorenstr 5, D-40225 Düsseldorf, Germany. E-mail schroer{at}pharma.uni-duesseldorf.de

Background—Previous studies have shown that thrombin is a potent though slow-acting mitogen for vascular smooth muscle cells (SMC). Because thrombin generation in vivo is accompanied by platelet activation, it has been suggested that platelet-derived factors might enhance thrombin-induced SMC proliferation. No information is available so far on the possible role of thromboxane A₂.

Methods and Results—Thrombin (1 U/mL) caused a threefold to fourfold increase of DNA synthesis in cultured bovine coronary artery SMC as assessed from [³H]thymidine incorporation. U 46619, a stable thromboxane A₂ mimetic, had only a minor stimulating effect on its own but potentiated the thrombin effect sixfold to sevenfold above control (P<.05). These findings were paralleled by a 52±5% (P<.05) increase in cell number at 48 hours after addition of both mitogens as compared with 24±5% with thrombin alone and no change with U 46619 alone. Thromboxane A₂ receptor mRNA was found to be upregulated sixfold 20 minutes after thrombin stimulation. Pretreatment of SMC with thrombin for 4 hours markedly increased U 46619–induced mitogen-activated protein kinase activity, indicating thrombin-induced upregulation of functional thromboxane receptors in SMC.

Conclusions—Thrombin-induced proliferation of SMC is markedly enhanced by thromboxane A₂. This might result in an enhancement of SMC proliferation by platelet-derived thromboxane A₂ in vivo.

Key Words: growth substances • cells • muscle, smooth

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