Mindin regulates vascular smooth muscle cell phenotype and prevents neointima formation.
Mindin regulates vascular smooth muscle cell phenotype and prevents neointima formation.
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Mindin 调节血管平滑肌细胞表型并防止新内膜形成。
DOI：
10.1042/cs20140679
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Li Hongliang
中科院分区：
文献类型：
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作者：
Zhu Li-Hua;Huang Ling;Zhang Xiaojing;Zhang Peng;Zhang Shu-Min;Guan Hongjing;Zhang Yan;Zhu Xue-Yong;Tian Song;Deng Keqiong;Li Hongliang
Mindin/spondin 2是一种属于1型血小板反应蛋白（TSR）分子的细胞外基质（ECM）组分，在炎症反应、血管生成和代谢紊乱的调节中起着重要作用。我们最近的研究表明，mindin主要参与心脏和脑血管疾病的起始和发展[Zhu等人（2014）J.Hepatol.60，1046-1054; Bian等人（2012）J. Mol. 90，895-910; Wang等人（2013）Exp. 247，506-516; Yan等人（2011）Neurovasc. Res.92，85-94]。然而，mindin在新生内膜形成中的调节功能仍不清楚。在本研究中，mindin的表达显着下调血小板衍生生长因子-BB（PDGF-BB）刺激的血管平滑肌细胞（VSMCs）和线损伤刺激的血管组织。使用功能获得方法，VSMC中mindin的过表达对VSMC表现出强烈的抗增殖和抗迁移作用，而在特异性表达mindin的转基因（TG）小鼠中观察到对内膜增生的显着抑制平滑肌细胞（SMC）。这些小鼠表现出钝VSMC增殖，迁移和表型转换。相反，mindin的缺失显著加剧了钢丝损伤小鼠模型中的新生内膜形成，这在使用新型mindin-KO（敲除）大鼠品系的球囊损伤诱导的血管病变模型中得到了进一步证实。从机制的角度来看，AKT（蛋白激酶B）-GSK 3 β（糖原合成酶激酶3β）/mTOR（雷帕霉素的哺乳动物靶蛋白）-FOXO 3A（叉头盒O）-FOXO 1信号传导轴负责内膜增厚期间mindin的调节。有趣的是，AKT抑制剂在很大程度上逆转了mindin-KO诱导的严重增生，表明mindin介导的新生内膜形成是AKT依赖性的。总之，我们的研究结果表明，mindin通过抑制异常VSMC增殖，迁移和表型转换以AKT依赖的方式保护血管增生。上调mindin的表达可能是治疗血管重塑相关疾病的有效方法。
Mindin/spondin 2, an extracellular matrix (ECM) component that belongs to the thrombospondin type 1 (TSR) class of molecules, plays prominent roles in the regulation of inflammatory responses, angiogenesis and metabolic disorders. Our most recent studies indicated that mindin is largely involved in the initiation and development of cardiac and cerebrovascular diseases [Zhu et al. (2014) J. Hepatol.60, 1046–1054; Bian et al. (2012) J. Mol. Med.90, 895–910; Wang et al. (2013) Exp. Neurol.247, 506–516; Yan et al. (2011) Cardiovasc. Res.92, 85–94]. However, the regulatory functions of mindin in neointima formation remain unclear. In the present study, mindin expression was significantly down-regulated in platelet-derived growth factor-BB (PDGF-BB)-stimulated vascular smooth muscle cells (VSMCs) and wire injury-stimulated vascular tissue. Using a gain-of-function approach, overexpression of mindin in VSMCs exhibited strong anti-proliferative and anti-migratory effects on VSMCs, whereas significant suppression of intimal hyperplasia was observed in transgenic (TG) mice expressing mindin specifically in smooth muscle cells (SMCs). These mice exhibited blunted VSMC proliferation, migration and phenotypic switching. Conversely, deletion of mindin dramatically exacerbated neointima formation in a wire-injury mouse model, which was further confirmed in a balloon injury-induced vascular lesion model using a novel mindin-KO (knockout) rat strain. From a mechanistic standpoint, the AKT (Protein Kinase B)−GSK3β (glycogen synthase kinase 3β)/mTOR (mammalian target of rapamycin)−FOXO3A (forkhead box O)–FOXO1 signalling axis is responsible for the regulation of mindin during intimal thickening. Interestingly, an AKT inhibitor largely reversed mindin-KO-induced aggravated hyperplasia, suggesting that mindin-mediated neointima formation is AKT-dependent. Taken together, our findings demonstrate that mindin protects against vascular hyperplasia by suppression of abnormal VSMC proliferation, migration and phenotypic switching in an AKT-dependent manner. Up-regulation of mindin might represent an effective therapy for vascular-remodelling-related diseases.