Protective Role of Clusterin/Apolipoprotein J Against Neointimal Hyperplasia via Antiproliferative Effect on Vascular Smooth Muscle Cells and Cytoprotective Effect on Endothelial Cells
- Affiliated Author(s)
- Alternative Author(s)
- Park, Keun Gyu
- Journal Title
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Issued Date
- Objective—Clusterin is induced in vascular smooth muscle cells (VSMCs) during atherosclerosis and injury-induced neointimal
hyperplasia. However, its functional roles in VSMCs and endothelial cells remain controversial and elusive. This study was
undertaken to clarify the role of clusterin in neointimal hyperplasia and elucidate its mechanism of action.
Methods and Results—Adenovirus-mediated overexpression of clusterin (Ad-Clu) repressed TNF- –stimulated expression
of MCP-1, fractalkine, ICAM-1, VCAM-1, and MMP-9, leading to inhibition of VSMC migration. Both Ad-Clu
and secreted clusterin suppressed VSMC proliferation by inhibiting DNA synthesis, but not by inducing apoptosis.
Ad-Clu upregulated p53 and p21cip1/waf1 but downregulated cyclins D and E, leading to suppression of pRb
phosphorylation and subsequent induction of G1 arrest in VSMCs. Clusterin deficiency augmented VSMC proliferation
in vitro and accelerated neointimal hyperplasia in vivo, but concomitantly impaired reendothelialization in wire-injured
murine femoral arteries. Moreover, Ad-Clu significantly reduced neointimal thickening in balloon-injured rat carotid
arteries. Clusterin also diminished TNF- –induced apoptosis of human umbilical vein endothelial cells and restored
endothelial nitric oxide synthase expression suppressed by TNF- .
Conclusion—These results suggest that upregulation of clusterin during vascular injury may be a protective response against, rather
than a causative response to, the development of neointimal hyperplasia. (Arterioscler Thromb Vasc Biol. 2009;29:1558-1564.)
Key Words: clusterin VSMC endothelial cells proliferation neointimal hyperplasia
- Authorize & License
- Files in This Item:
Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.