Thrombin-induced mitogenesis in coronary artery smooth muscle cells is potentiated by thromboxane A2 and involves upregulation of thromboxane receptor mRNA.
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.


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.
Zucker
T P
TP
Institut für Klinische Anaesthesiologie, Heinrich-Heine-Universität Düsseldorf, Germany.
Bönisch
D
D
Muck
S
S
Weber
A A
AA
Bretschneider
E
E
Glusa
E
E
Schrör
K
K
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D005260:Female; D008938:Mitosis / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000494:pharmacology*; D015854:Up-Regulation
D012333:RNA, Messenger; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013917:Thrombin