| Project/Area Number |
16590868
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Chiba University |
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Principal Investigator |
YOKOTE Koutaro Chiba University, Hospital, Research associate, 医学部附属病院, 助手 (20312944)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | TGF-β / Smad3 / Atherosclerosis / Intracellular signal transduction / matrix / bone marrow transplantation / smooth muscle cells / macrophage |
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| Research Abstract |
The role of TGF-β in atherogenesis has been the subject of debate. Recent results of animal experiments suggest that TGF-β is protective against lipid lesion formation but promotes restenosis through enhancement of ECM deposition. In order to clarify the role of Smad3-dependent signal in atherogenesis, we examined vascular lesions in mice lacking Smad3 by use of endothelial injury and hypercholesterolemia models.
Thrombotic endothelial injury resulted in significant enhancement of neointimal hyperplasia in femoral arteries of Smad3-null (null) compared to wild-type mice. Transplantation of null bone marrow to wild-type mice did not enhance neointimal thickening, suggesting that vascular cells in situ play a major role in the response. Null intima contained more proliferating SMCs with less amount of collagen compared to wild-type intima. TGF-β caused significant inhibition of cellular proliferation in wild-type aortic SMCs, whereas the growth of null SMCs was only weakly inhibited by TG
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F-β in vitro, indicating a crucial role of Smad3 in the growth inhibitory function. In contrast, Smad3-deficiency did not attenuate migration of SMCs towards TGF-β. TGF-β increased transcript level of α2 type I collagen and tissue inhibitor of metalloproteinases-1, and suppressed expression and activity of matrix metalloproteinases in wild-type SMCs. However, these effects of TGF-β were diminished in null SMCs.
Atheromatous lesion was evaluated in hypercholesterolemic Smad3-null/ApoE-null mice generated by cross mating. The double knockout mice showed markedly enhanced "unstable-like" aortic plaques rich in foamy macrophages compare to the control ApoE-null mice. The exaggerated macrophage accumulation in intima coincided with upregulation of monocyte chemoattractant protein-1 (MCP-1). In addition, in vitro results suggested that Smad3 is required for the suppressive effect of TGF-β on MCP-1 expression in macrophages.
Our findings altogether indicate that the loss of Smad3 signal facilitates neointimal lesion formation in response to various atherosclerotic stimuli, suggesting an anti-atherosclerotic role of endogenous Smad3. Less
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