Arterial gene transfer of the TGF-β signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF
Arterial gene transfer of the TGF-β signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF
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DOI：
10.1093/cvr/cvp220
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发表时间：
2009-11-01
影响因子：
10.8
通讯作者：
Kent, K. Craig
中科院分区：
文献类型：
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作者：
Kundi, Rishi;Hollenbeck, Scott T.;Kent, K. Craig
虽然转化生长因子-β（TGF-β）被认为是刺激动脉损伤后内膜增生，其在重塑中的作用仍不清楚。我们调查是否Smad 3，TGF-β信号蛋白，可能促进其对remodelling.Methods和结果的影响使用大鼠颈动脉血管成形术模型，我们评估Smad 3表达动脉损伤后。然后，我们测试动脉Smad 3过度表达对损伤的反应的影响，并使用条件培养基实验设计，以确认Smad 3依赖性可溶性因子介导这种反应。我们使用小干扰RNA（siRNA）鉴定该因子为结缔组织生长因子（CTGF）。最后，我们试图复制medial的效果。通过外膜应用重组CTGF的Smad 3过表达。内侧损伤。Smad 3的表达; Smad 3的过表达引起新生内膜增厚和管腔扩张，表明适应性重塑。Smad 3过表达，尽管仅限于内侧。，引起外膜变化：肌成纤维细胞转化、增殖和胶原蛋白产生，所有这些都与适应性重塑有关。支持Smad 3通过中膜的分泌产物启动重塑和这些外膜变化的假设。平滑肌细胞（SMCs）中，我们发现由表达Smad 3的重组腺病毒载体（AdSmad 3）感染的SMCs条件培养基刺激体外外膜成纤维细胞转化、增殖和胶原产生。这种作用被衰减预处理的SMCs与CTGF特异性的siRNA，大量产生的AdSmad 3感染的SMCs，并显着上调Smad 3过表达的动脉。此外，外膜周施用CTGF复制了中膜的效果。结论Smad 3基因转染可通过间接影响外膜成纤维细胞的行为，促进适应性重塑。这种动脉细胞间的通讯可能是由Smad 3依赖的CTGF产生介导的。
Aims Although transforming growth factor-beta (TGF-beta) is believed to stimulate intimal hyperptasia after arterial injury, its rote in remodelling remains unclear. We investigate whether Smad3, a TGF-beta signalling protein, might facilitate its effect on remodelling.Methods and results Using the rat carotid angioplasty model, we assess Smad3 expression following arterial injury. We then test the effect of arterial Smad3 overexpression on the response to injury, and use a conditioned media experimental design to confirm an Smad3-dependent soluble factor that mediates this response. We use small interfering RNA (siRNA) to identify this factor as connective tissue growth factor (CTGF). Finally, we attempt to replicate the effect of medial. Smad3 overexpression through adventitial application of recombinant CTGF. Injury induced medial. expression of Smad3; overexpression of Smad3 caused neointimal thickening and luminal expansion, suggesting adaptive remodelling. Smad3 overexpression, though exclusively medial., caused adventitial changes: myofibroblast transformation, proliferation, and collagen production, all of which are associated with adaptive remodelling. Supporting the hypothesis that Smad3 initiated remodelling and these adventitial changes via a secreted product of medial. smooth muscle cells (SMCs), we found that media conditioned by Smad3-expressing recombinant adenoviral vector (AdSmad3)-infected SMCs stimulated adventitial fibroblast transformation, proliferation, and collagen production in vitro. This effect was attenuated by pre-treatment of SMCs with siRNA specific for CTGF, abundantly produced by AdSmad3-infected SMCs, and significantly up-regulated in Smad3-overexpressing arteries. Moreover, periadventitial administration of CTGF replicated the effect of medial. Smad3 overexpression on adaptive remodelling and neointimal hyperplasia.Conclusion Medial gene transfer of Smad3 promotes adaptive remodelling by indirectly influencing the behaviour of adventitial fibroblasts. This arterial cell-cell communication is likely to be mediated by Smad3-dependent production of CTGF.