Protective Role of Clusterin/Apolipoprotein J Against Neointimal Hyperplasia via Antiproliferative Effect on Vascular Smooth Muscle Cells and Cytoprotective Effect on Endothelial Cells

Han-Jong KimEun-Kyung Yoooon-Young KimYoung-Keun ChoiHyo-Jeong LeeJeong-Kook KimNam Ho JeoungKi-Up LeeIn-Sun ParkBon-Hong MinKeun-Gyu ParkChul-Ho LeeBruce J. AronowMasataka SataIn-Kyu Lee
Dept. of Internal Medicine (내과학)
Issue Date
Arteriosclerosis, Thrombosis, and Vascular Biology, Vol.29(10) : 1558-1564, 2009
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
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