Background: 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. Methods: 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 InfiltratorTM, 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. 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 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. Conclusions: 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.
Bibliographical noteFunding Information:
This study was supported by the Korea Research Foundation Grant KRF-2000-003-F00030 (Dr. Chung), the Korean Society of Circulation Industry and Academy Grant 99-5 (Dr. Chung), and NIH HL 18645 (Dr. Wight). We appreciate Dr. Stephen M Schwartz (University of Washington, WA) for advice, Dr. Ki-Bum Lee (Ajou University Medical Center, Korea) for technical support for cutting stented arteries, and Dr. Chan Park (NIH, Seoul, Korea) for advice of adenovirus propagation. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology  .
All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine