INVOLVEMENT OF NF-KAPPA-B ACTIVATION IN THROMBIN-INDUCED HUMAN VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION

A thrombin receptor has been cloned and is thought to mediate a variet y of thrombin-induced responses. However, the transcription factors im portant for postreceptor signaling have been little clarified. The pos t-receptor signals are mediated by several protein kinases responsible for NF-KB activation, and most thrombin-inducible genes have the KB s equence in the regulatory elements, The possibility that NF-kappa B ma y participate in thrombin signaling was therefore investigated in cult ured human vascular smooth muscle cells (VSMCs). Thrombin receptor sti mulation resulted in activation of NF-kappa B. Furthermore, treatment of cells with antisense p65 ODNs of NF-kappa B inhibited thrombin-stim ulated growth of VSMC in vitro. Results indicate that the activation o f NF-kappa B is involved in thrombin signaling and that this pathway c auses the proliferation of VSMC induced by thrombin. Therapeutic poten tial of antisense NF-kappa B ODNs for the treatment with atheroscleros is and restenosis is also indicated. (C) 1994 Academic Press, Inc.