Kim Han-Jong, Yoo Eun-Kyung, Kim Joon-Young, Choi Young-Keun, Lee Hyo-Jeong, Kim Jeong-Kook, Jeoung Nam Ho, Lee Ki-Up, Park In-Sun, Min Bon-Hong, Park Keun-Gyu, Lee Chul-Ho, Aronow Bruce J, Sata Masataka, Lee In-Kyu
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, South Korea.
Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1558-64. doi: 10.1161/ATVBAHA.109.190058. Epub 2009 Aug 20.
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.
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.
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.
在动脉粥样硬化和损伤诱导的内膜增生过程中，血管平滑肌细胞（VSMC）会诱导产生聚集素。然而，其在VSMC和内皮细胞中的功能作用仍存在争议且尚不明确。本研究旨在阐明聚集素在内膜增生中的作用并阐明其作用机制。
腺病毒介导的聚集素过表达（Ad-Clu）抑制了肿瘤坏死因子-α（TNF-α）刺激的单核细胞趋化蛋白-1（MCP-1）、 fractalkine、细胞间黏附分子-1（ICAM-1）、血管细胞黏附分子-1（VCAM-1）和基质金属蛋白酶-9（MMP-9）的表达，从而抑制了VSMC迁移。Ad-Clu和分泌型聚集素均通过抑制DNA合成而非诱导凋亡来抑制VSMC增殖。Ad-Clu上调p53和p21（cip1/waf1），但下调细胞周期蛋白D和E，导致VSMC中视网膜母细胞瘤蛋白（pRb）磷酸化受到抑制，随后诱导G1期阻滞。聚集素缺乏会增强体外VSMC增殖并加速体内内膜增生，但同时会损害丝线损伤的小鼠股动脉中的再内皮化。此外，Ad-Clu显著减少了球囊损伤的大鼠颈动脉中的内膜增厚。聚集素还减少了TNF-α诱导的人脐静脉内皮细胞凋亡，并恢复了被TNF-α抑制的内皮型一氧化氮合酶表达。
这些结果表明，血管损伤期间聚集素的上调可能是对内膜增生发展的一种保护反应，而非致病反应。
