| Project/Area Number |
12670141
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pathological medical chemistry
|
|---|
| Research Institution | Nagasaki University |
|---|
Principal Investigator |
URATA Yoshishige Department of Biochemistry and Molecular Biology in Disease, Atomic Disease Institute, Nagasaki University, Assistant, 医学部, 助手 (30185087)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KONDO Takahito Department of Biochemistry and Molecular Biology in Disease, Atomic Disease Institute, Nagasaki University, Professor, 医学部, 教授 (00158908)
IHARA Yoshito Department of Biochemistry and Molecular Biology in Disease, Atomic Disease Institute, Nagasaki University, Lecturer, 医学部, 講師 (70263241)
GOTO Shinzi Department of Biochemistry and Molecular Biology in Disease, Atomic Disease Institute, Nagasaki University, Research Associate, 医学部, 助手 (50186889)
|
|---|
| Project Period (FY) |
2000 – 2001
|
| Project Status |
Completed (Fiscal Year 2001)
|
| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥2,600,000 (Direct Cost: ¥2,600,000)
|
|---|
| Keywords | γ-GCS / VEGF / RZR / ROR / activator protein-1 / ERK1 / 2 / メラトニン / 血管内皮増殖因子 / グルタチオン |
|---|
| Research Abstract |
Advanced glycation end products (AGEs) are believed to play an important role in the development of angiopathy in diabetes mellitus. Previous reports suggested a correlation between accumulation of AGEs and production of vascular endothelial growth factor (VEGF) in human diabetic retina. However, the mechanisms involved were not revealed. In this study, we investigated the transcriptional reg ulation of the expression of vascular endothelial growth factor (VEGF) by AGEs, and possible involve ment of reactive oxygen species (EOS) in the induction. We employed an AGE of bovine serum albumin (BSA) prepared by an incubation of BSA with D-glucose for 40 weeks and N(epsilon) (carboxymethyl)lysine (CML), a major AGE. The expression ofVEGF was induced by CML-BSA in RAW264.7 mouse macrophage like cells. CML-BSA stimulated the DNA-binding activity of activator protein- 1 (AP-1). Promoter assay showed that the induction of VEGFwas dependent on AP- 1. The activity of Ras/ Raf- II MEK/ ERK1/2 was involved in the CML-BSA-stimulated signaling pathways to activate the AP-1 transcription with a peak at 1 h. AGE-BSA also induced VEGF mediated by AP-1, however, there was a difference of effect between AGE-BSA and CML-BSA in the activation ofAP-1. AGE-BSA-stimulated AP-1 activity showed a peak at 5 h, which paralleled the formation of ROS. Reduction of AGE-BSA with NaBH4 or addition of vitamin E attenuated the AGE-BSA-stimulated signaling pathways leading to the same pattern as for CML-BSA-stimulated signals. These results suggest an important role for AGEs in stimulation of the development of angiogenesis observed in dia betic complications, and that ROS accelerates the AGE-stimulated VEGF expression.
|
