Protective role of clusterin/apolipoprotein J against neointimal hyperplasia via antiproliferative effect on vascular smooth muscle cells and cytoprotective effect on endothelial cells.
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.


RESULTS
Adenovirus-mediated overexpression of clusterin (Ad-Clu) repressed TNF-alpha-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 p21(cip1/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-alpha-induced apoptosis of human umbilical vein endothelial cells and restored endothelial nitric oxide synthase expression suppressed by TNF-alpha.


CONCLUSIONS
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.
Kim
Han-Jong
HJ
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, South Korea.
Yoo
Eun-Kyung
EK
Kim
Joon-Young
JY
Choi
Young-Keun
YK
Lee
Hyo-Jeong
HJ
Kim
Jeong-Kook
JK
Jeoung
Nam Ho
NH
Lee
Ki-Up
KU
Park
In-Sun
IS
Min
Bon-Hong
BH
Park
Keun-Gyu
KG
Lee
Chul-Ho
CH
Aronow
Bruce J
BJ
Sata
Masataka
M
Lee
In-Kyu
IK
D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D051152:Clusterin / Q000502:physiology*; D019610:Cytoprotection; D004247:DNA / Q000096:biosynthesis; D042783:Endothelial Cells / Q000166:cytology*; D016193:G1 Phase; D006965:Hyperplasia; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016160:Retinoblastoma Protein / Q000378:metabolism; D017539:Tunica Intima / Q000473:pathology*
C498500:Clu protein, rat; D051152:Clusterin; D016328:NF-kappa B; D016160:Retinoblastoma Protein; D004247:DNA; D020780:Matrix Metalloproteinase 9