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

Abstract 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 block...

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Published in:International journal of cardiology 2010-12, Vol.145 (3), p.468-475
Main Authors: Chung, Ick-Mo, Kim, Junwoo, Pak, Youngmi K, Jang, Yangsoo, Yang, Woo-Ick, Han, Innoc, Park, Seung-Jung, Park, Seong-Wook, Huh, Jooryung, Wight, Thomas N, Ueno, Hikaru
Format: Article
Language:English
Subjects:
Adenovirus
Angioplasty
Animals
Biological and medical sciences
Cardiology. Vascular system
Cardiovascular
Catheterization
CD3 Complex - metabolism
Cells, Cultured
Connective Tissue Growth Factor - genetics
Coronary Artery Disease - therapy
Female
Gene Transfer Techniques
Hyaluronan
Hyaluronic Acid - metabolism
In Vitro Techniques
Inflammation
Male
Matrix Metalloproteinase 1 - metabolism
Medical sciences
Muscle, Smooth, Vascular - cytology
Muscle, Smooth, Vascular - physiology
Neointima - therapy
Protein-Serine-Threonine Kinases - genetics
Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects)
Rats
Rats, Sprague-Dawley
Receptor, Transforming Growth Factor-beta Type II
Receptors, Transforming Growth Factor beta - genetics
Restenosis
Stents
Stents - adverse effects
Swine
T-Lymphocytes - cytology
Transforming Growth Factor beta - antagonists & inhibitors
Transforming growth factor-β
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Summary:Abstract 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.
ISSN:0167-5273
1874-1754
DOI:10.1016/j.ijcard.2009.11.032