[Study of signal transduction through thrombin receptor and anti-thrombotic strategy using its controls]

Thrombin, a key enzyme in the hemostatic pathway, also has various effects on the function of human platelet, endothelial cells (HUVEC) and vascular smooth muscle cells (VSMC). A thrombin receptor (TR) has been cloned and is thought to mediate a variety of thrombin-induced responses. The post-receptor signals are mediated by several protein kinases responsible for NF-kappa B activation, and most thrombin-inducible genes have the kappa B sequence in the regulatory elements. TR stimulation resulted in a biphasic activation of NF-kappa B and the late phase of which required new NF-kappa B synthesis. We showed that the antisense oligodeoxynucleotides (ODNs) of NF-kappa B have a marked inhibitory effect on thrombin-induced cellular responses. Furthermore, E5510, a compound with anti-platelet activity preferentially inhibited the thrombin-inducible NF-kappa B activation. Therapeutic potential of inhibition of TR-NF-kappa B activation signaling for treatment with thrombotic disease is also indicated.