title: Protective role of clusterin/apolipoprotein J against neointimal hyperplasia via antiproliferative effect on vascular smooth muscle cells and cytoprotective effect on endothelial cells.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, South Korea.
authors.forename: Han-Jong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Yoo
authors.forename: Joon-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Young-Keun
authors.initials: YK
authors.lastname: Choi
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Jeong-Kook
authors.initials: JK
authors.lastname: Kim
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Jeoung
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Park
authors.forename: Bon-Hong
authors.initials: BH
authors.lastname: Min
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: 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*
chemical_list: C498500:Clu protein, rat; D051152:Clusterin; D016328:NF-kappa B; D016160:Retinoblastoma Protein; D004247:DNA; D020780:Matrix Metalloproteinase 9