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Cardiovascular Research 1998 38(1):263-271; doi:10.1016/S0008-6363(97)00296-4
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Thrombin receptor expression is increased by angiotensin II in cultured and native vascular smooth muscle cells

Beate Fisslthaler*, Valerie B Schini-Kerth, Ingrid Fleming and Rudi Busse

Institut für Kardiovaskuläre Physiologie, Klinikum der Johann Wolfgang Goethe Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany

* Corresponding author. Tel.: +49 (69) 6301-6995; Fax: +49 (69) 6301-7668; E-mail: fisslthaler@em.uni-frankfurt.de

Objective: The factors involved in restenosis after balloon angioplasty are poorly characterized but the local concentration of the potent mitogens angiotensin II (AII) and thrombin is known to be increased at sites of vascular injury. We investigated the possibility of a synergistic interaction between AII and thrombin by studying the effects of AII on the expression of the thrombin receptor in rat aortic smooth muscle cells (VMSC). Methods: Thrombin receptor mRNA expression was studied by Northern blot analysis and RT-PCR using total RNA extracted from VMSC or from endothelium-denuded rat aortae. As a measure of thrombin receptor protein expression, we assessed either the thrombin-stimulated release of 6-keto-prostaglandin F1{alpha} from VMSC or the contraction of endothelium-denuded rat aortic rings. Results: The thrombin receptor mRNA was expressed at a low level in both cultured and native VMSC. AII concentration- and time-dependently increased expression of thrombin receptor mRNA in VSMC and augmented the thrombin-induced release of 6-keto-prostaglandin F1{alpha} as well as the thrombin-induced contraction. Blockade of the angiotensin subtype 1 (AT1) receptor by EXP3174 or D8731 prevented the AII-mediated increase in thrombin receptor expression. The effect of AII on the increase in thrombin receptor mRNA expression was enhanced by the protein kinase C inhibitor Ro 31-8220, but was unaffected by prolonged incubation with phorbol myristate acetate or the tyrosine kinase inhibitors genistein and erbstatin A. Conclusion: These results demonstrate that AII enhances the expression of thrombin receptor in cultured and native VMSC. In cultured cells, this effect is mediated by the activation of the AT1 receptor subtype. This synergistic effect between AII and the thrombin receptor may promote the extensive proliferation of smooth muscle cells in response to vascular injury.

KEYWORDS Rat aortic smooth muscle cell; Restenosis; Angiotensin II; Thrombin receptor; Tyrosine kinase inhibitor; AT1 receptor; Protein kinase C


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