| Project/Area Number |
07457174
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Circulatory organs internal medicine
|
|---|
| Research Institution | Kagoshima University |
|---|
Principal Investigator |
KITAJIMA Isao Faculty of Medicine Kagoshima University, Associate Professor, 医学部, 助教授 (50214797)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
YONEZAWA Suguru Faculty of Medicine Kagoshima University, Associate Professor, 医学部, 助教授 (10175002)
AKASHI Mitsuru Faculty of Medicine Kagoshima University, Professor, 工学部, 教授 (20145460)
MARUYAMA Ikuro Faculty of Medicine Kagoshima University, Professor, 医学部, 教授 (20082282)
|
|---|
| Project Period (FY) |
1995 – 1996
|
| Project Status |
Completed (Fiscal Year 1996)
|
| Budget Amount *help |
¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1996: ¥1,600,000 (Direct Cost: ¥1,600,000)
|
|---|
| Keywords | Artherosclerosis / Vascular smooth muscle cell / Transcription factor / NF-kappaB / Genetherapy / Antisense oligo / Mouse / Aramid-silicon / 血管平滑筋細胞 / トロンビン / LPS / エンドトキシンショック / 人工血管 / 血管内皮細胞 / NF-_KB |
|---|
| Research Abstract |
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.
|
