Basic and clinical research of a novel atherosclerosis-specific gene for the promotion of health science
| Project/Area Number |
17300225
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied health science
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| Research Institution | Mukogawa Women's University |
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Principal Investigator |
FUKUO Keisuke Mukogawa Women's University, School of Human Environmental Sciences, Professor (40156758)
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| Co-Investigator(Kenkyū-buntansha) |
FUKADA Rumi Mukogawa Women's University, School of Human Environmental Sciences, Assistant (60399136)
YASUDA Osamu Osaka University Medical School, Geriatric Medicine, Associate (00372615)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥15,880,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2007: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2006: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2005: ¥5,500,000 (Direct Cost: ¥5,500,000)
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| Keywords | Ageing / Oxidative Stress / Mitochondria / Atherosclerosis / Apoptosis / 血管平滑筋細胞 / 遺伝子 |
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| Research Abstract |
Here, we describe a novel and evolutionarily conserved protein, apoptogenic protein (Apop). Mouse Apop-1 expression induces apoptotic death by releasing cytochrome c from mitochondria into the cytosolic space followed by activation of caspase-9 and -3. Apop-1-induced apoptosis is not blocked by Bc1-2 or Bcl-xL, inhibitors of Bax/Bak-dependent channels, whereas it is completely blocked by cyclosporin A, an inhibitor of permeability transition pore. Cells lacking CypD were resistant to Apop-induced apoptosis. Moreover inhibition of Apop expression prevented the cell death induced by apoptosis-inducing substances. Our findings, thus, indicate that the expression of Apop-1 induces apoptosis though CypD-dependent pathway and that Apop-1 plays roles in cell death under physiological conditions. Vascular ageing is accelerated in patients with diabetes. However, the underlying mechanism remains unclear. Here, we also show that high glucose induces activation of apoptosis signal-regulating kina
… More
se 1(ASK1), an apoptosis-inducing signal that mediates endothelial cell senescence induced by hyperglycemia. High glucose induced a time-dependent increase in the levels of ASK1 expression and its activity in human umbilical vein endothelial cells (HUVECs). Incubation of endothelial sells with high glucose increased the proportion of cells expressing senescence-associated beta-galactosidase (SA-beta-gal) activity However, transfection with an adenoviral construct including a dominant negative form of ASK1 gene significantly inhibited SA-beta-gal activity induced by high glucose. In addition, infection with an adenoviral construct expressing the constitutively active ASK1 gene directly induced an increase in the levels of SA-beta-gal activity. Activation of the ASK1 signal also enhanced plasminogen activator inhibitor-1 (PAI-1) expression in HUVECs. Induction of senescent endothelial cells in aortas and elevation of plasma PAI-1 levels were observed in streptozotocin (SIZ) diabetic mice, whereas these changes induced by STZ were attenuated in ASK1-knockout mice. Our results suggest that hyperglycemia accelerates endothelial cell senescence and upregulation of PAI-1 expression through activation of the ASK1 signal. Thus, ASK1 may be a new therapeutic target to prevent vascular ageing and thrombosis in diabetic patients. Less
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Report
(4 results)
Research Products
(102 results)
