Blockade of TGF-β by catheter-based local intravascular gene delivery does not alter the in-stent neointimal response, but enhances inflammation in pig coronary arteries

[摘要] Background: Extracellular matrix (ECM) accumulation significantly contributes to in-stent restenosis. In this regard, transforming growth factor (TGF)-beta, 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-beta on stent-induced restenosis in porcine coronary arteries. Methods: An adenovirus expressing the ectodomain of the TGF-beta type II receptor (AdT beta-ExR) was applied onto a coronary arterial segment of a pig (n = 10) using an Infiltrator (TM), followed by stent deployment. Controls consisted of adenoviruses expressing beta-galactosidase (AdLacZ) or phosphate-buffered saline (PBS) applied onto the other segment (n = 10) of the same pig. Results: 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 AdT beta-ExR group and control (n = 7 for each). However the AdT beta-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 AdT beta-ExR at moi 60. Conclusions: Blockade of TGF-beta 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. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

[发布日期] 2010-12-03

[关键词] Hyaluronan;Inflammation;Restenosis;Stents;Transforming growth factor-beta