Gene therapy for atherosclerosis by inhibition of nuclear transcriptional factor

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The proliferation of vascular smooth muscle cells (VSMCs) is the most crucial cause of artherosclerosis. High expression of thrombin receptor (TR) in athrosclerotic lesions indicates a possible role for athrogenesis. In the present study, we demonstrated that post TR signaling were mediated by several protein kinases resposible for nuclear transcriptional factor, NF-kappaB activation and thrombin-inducible genes had the kappaB sequence in the regulatory elements. Thrombin stimulation in VSMCs resulted in a biphasic activation of NF-kappaB,the early phase of which indicated nuclear translocation of NF-kappaB and the late phase of which required new synthesis, resulting in proliferation of VSMC.Furthermore, treatment of VSMCs with antisense p65 oligodeoxynucleotides (ODNs) of NF-kappaB inhibited thrombin-stimulated growth of VSMCs in vitro. Next, we examined whether the antisense ODNs for NF-kappaB could affect in vivo. We used the mouse model of lipopolysaccharide (LPS) induced septic shock, because it is associated with activation of NF-kappaB.We showed that all mice treated with LPS ultimately died within 48 hrs, while mice pretreated with the antisense NF-kappaB ODNs had a significantly better outcome and the survival rate was 60%. This suggested the greatest advantage antisense NF-kappaB provides an important new therapeutic approach for the treatment with athrerosclerosis and LPS-induced septic shock in vitro and in vivo. Moreover, we have studied a novel biomaterial vessle using aramid-silicon to intruduce the antisense ODNs.