Division of Cardiology, Ewha Medical Research Institute, School of Medicine, Ewha Womans University, Ewha Womans University Mokdong Hospital, Seoul, Republic of Korea.
Int J Cardiol. 2010 Dec 3;145(3):468-75. doi: 10.1016/j.ijcard.2009.11.032. Epub 2010 Jan 6.
Extracellular matrix (ECM) accumulation significantly contributes to in-stent restenosis. In this regard, transforming growth factor (TGF)-β, a positive regulator of ECM deposition, may be implicated in in-stent restenosis. The goal of this study was to assess the effect of blockade of TGF-β on stent-induced restenosis in porcine coronary arteries.
An adenovirus expressing the ectodomain of the TGF-β type II receptor (AdTβ-ExR) was applied onto a coronary arterial segment of a pig (n=10) using an Infiltrator, followed by stent deployment. Controls consisted of adenoviruses expressing β-galactosidase (AdLacZ) or phosphate-buffered saline (PBS) applied onto the other segment (n=10) of the same pig.
Computer-based pathological morphometric analysis of stented coronary arteries, performed 4 weeks after stenting, demonstrated no significant difference in morphometric parameters such as in-stent neointimal area and % area stenosis between the AdTβ-ExR group and control (n=7 for each). However the AdTβ-ExR group had increased neointimal cell density, infiltration of inflammatory cells mostly consisting of CD3+ T cell, accumulation of hyaluronan, cell proliferation rate, and adventitial matrix metalloproteinase-1 (MMP-1) expression compared with control. The expression of connective tissue growth factor mRNA, measured by reverse transcription PCR, in cultured rat arterial smooth muscle cells was inhibited by AdTβ-ExR at moi 60.
Blockade of TGF-β by catheter-based local intravascular gene delivery does not reduce stent-induced neointima formation 4 weeks after stenting in spite of modest inhibition of ECM accumulation, but it induces vascular inflammation and associated pathological changes that may potentially aggravate lesion progression.
细胞外基质（ECM）的积累显著促进了支架内再狭窄。在这方面，转化生长因子（TGF）-β，一种 ECM 沉积的正调节剂，可能与支架内再狭窄有关。本研究的目的是评估阻断 TGF-β对猪冠状动脉支架内再狭窄的影响。
用 Infiltrator 将表达 TGF-β 型 II 受体胞外结构域的腺病毒（AdTβ-ExR）应用于猪的一段冠状动脉（n=10），然后进行支架置入。对照组包括表达β-半乳糖苷酶（AdLacZ）或磷酸盐缓冲盐水（PBS）的腺病毒，应用于同一猪的另一段冠状动脉（n=10）。
支架置入 4 周后，对支架置入的冠状动脉进行基于计算机的病理形态计量学分析，支架内新生内膜面积和%狭窄面积等形态计量学参数在 AdTβ-ExR 组和对照组之间无显著差异（每组 n=7）。然而，与对照组相比，AdTβ-ExR 组新生内膜细胞密度增加，炎症细胞浸润主要由 CD3+T 细胞组成，透明质酸积聚，细胞增殖率和外膜基质金属蛋白酶-1（MMP-1）表达增加。通过逆转录 PCR 测量，在培养的大鼠动脉平滑肌细胞中，AdTβ-ExR 以 moi 60 抑制结缔组织生长因子 mRNA 的表达。
尽管 ECM 积聚的抑制作用适度，但通过导管内局部血管内基因传递阻断 TGF-β不能减少支架置入后 4 周的支架内新生内膜形成，但它诱导血管炎症和相关的病理变化，可能潜在地加重病变进展。
