Published online before print August 20, 2009, doi: 10.1161/ATVBAHA.109.190058
© 2009 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Protective Role of Clusterin/Apolipoprotein J Against Neointimal Hyperplasia via Antiproliferative Effect on Vascular Smooth Muscle Cells and Cytoprotective Effect on Endothelial Cells
From the Department of Internal Medicine, and Biochemistry and Cell Biology (H.-J.K., E.-K.Y., J.-Y.K., H.-J.L., J.-K.K., N.H.J., I.-K.L.), Kyungpook National University School of Medicine, Daegu, Korea; the Department of Internal Medicine (Y.-K.C., K.-G.P.), Keimyung University School of Medicine, Daegu, Korea; the Department of Internal Medicine and Asan Institute for Life Sciences (K.-U.L.), University of Ulsan College of Medicine, Seoul, Korea; the Department of Anatomy and Center for Advanced Medical Education by BK21 project (I.-S.P.), College of Medicine, Inha University, Incheon, Korea; the Department of Pharmacology and BK21 Program for Medical Sciences (B.-H.M.), College of Medicine, Korea University, Seoul, Korea; the Laboratory of Experimental Animals (C.-H.L.), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea; the Division of Developmental Biology (B.J.A.), Children’s Hospital Medical Center, Cincinnati, Ohio; and the Department of Cardiovascular Medicine (M.S.), Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. Current affiliation for N.H.J.: the Department of Fundamental Medical Sciences, Catholic University of Daegu, Korea.
Correspondence to In-Kyu Lee, MD, PhD, Department of Internal Medicine, Kyungpook National University School of Medicine, #50 Samduk-2Ga, Jung-Gu, Daegu 700-721, South Korea. E-mail leei{at}knu.ac.kr
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.
Although clusterin is induced in VSMCs during atherosclerosis and postinjury restenosis, its exact function in the development of neointimal hyperplasia remains elusive. Here, we demonstrate that clusterin plays a protective role against neointimal hyperplasia through its antiproliferative and antimigratory action on VSMCs and through cytoprotective effect on endothelial cells.
Key Words: clusterin • VSMC • endothelial cells • proliferation • neointimal hyperplasia