Chen Jiyuan, Chada Sunil, Mhashilkar Abner, Miano Joseph M
Center for Cardiovascular Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 679, Rochester, New York 14642, USA.
Mol Ther. 2003 Aug;8(2):220-9. doi: 10.1016/s1525-0016(03)00176-x.
Abnormalities in smooth muscle cell (SMC) proliferation and differentiation underlie the pathogenesis of proliferative vascular diseases. MDA-7 (HUGO approved symbol IL24) is a unique gene, originally identified as a tumor suppressor and more recently shown to have cytokine activity. MDA-7/IL24 has been implicated in apoptosis and cellular differentiation in tumor cells and in tumor invasion/metastasis in clinical specimens-properties central to SMC remodeling during proliferative vascular diseases. In this study, we evaluated the effects of overexpressing MDA-7/IL24 in various SMC: the apparently "normal" rat PAC1 cell line, primary human coronary artery SMC, and normal rat aortic SMC. We transduced SMC with adenovirus-mda7 (Ad-mda7) or control virus (Ad-Luc) and assessed cell viability, apoptosis, and migration. Ad-mda7 suppressed PAC1 cell growth in a dose-dependent manner while having no effect on normal primary human coronary artery cells or rat aortic SMC, despite strong expression of the MDA-7 transgene in all SMC. Similarly, Ad-mda7 treatment induced apoptosis in PAC1 cells with essentially no effect on normal coronary and rat aortic SMC. Ad-mda7 also inhibited serum-stimulated PAC1 cell migration. Karyotype analysis of PAC1 cells revealed that they exhibit multiple chromosomal aberrations. Importantly, recombinant MDA-7 did not elicit cell death or STAT-3 activation in PAC1 SMC, suggesting that the effects of Ad-mda7 were mediated through an intracellular pathway. These data demonstrate that Ad-mda7 exhibits selectivity in apoptosis induction and growth suppression in an atypical SMC line, raising new questions pertaining to heterogeneity in SMC death susceptibility.
平滑肌细胞（SMC）增殖和分化异常是增殖性血管疾病发病机制的基础。MDA-7（HUGO批准符号IL24）是一个独特的基因，最初被鉴定为肿瘤抑制因子，最近发现它具有细胞因子活性。MDA-7/IL24与肿瘤细胞的凋亡和细胞分化以及临床标本中的肿瘤侵袭/转移有关，这些特性是增殖性血管疾病中SMC重塑的核心。在本研究中，我们评估了在各种SMC中过表达MDA-7/IL24的效果：明显“正常”的大鼠PAC1细胞系、原代人冠状动脉SMC和正常大鼠主动脉SMC。我们用腺病毒-mda7（Ad-mda7）或对照病毒（Ad-Luc）转导SMC，并评估细胞活力、凋亡和迁移。Ad-mda7以剂量依赖性方式抑制PAC1细胞生长，而对正常原代人冠状动脉细胞或大鼠主动脉SMC没有影响，尽管MDA-7转基因在所有SMC中均有强烈表达。同样，Ad-mda7处理诱导PAC1细胞凋亡，而对正常冠状动脉和大鼠主动脉SMC基本没有影响。Ad-mda7还抑制血清刺激的PAC1细胞迁移。PAC1细胞的核型分析显示它们存在多个染色体畸变。重要的是，重组MDA-7未在PAC1 SMC中引发细胞死亡或STAT-3激活，这表明Ad-mda7的作用是通过细胞内途径介导的。这些数据表明，Ad-mda7在非典型SMC系的凋亡诱导和生长抑制方面表现出选择性，这就引发了关于SMC死亡易感性异质性的新问题。
