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.
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 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.


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.
Chung
Ick-Mo
IM
Division of Cardiology, Ewha Medical Research Institute, School of Medicine, Ewha Womans University, Ewha Womans University Mokdong Hospital, Seoul, Republic of Korea. ickmo@ewha.ac.kr
Kim
Junwoo
J
Pak
Youngmi K
YK
Jang
Yangsoo
Y
Yang
Woo-Ick
WI
Han
Innoc
I
Park
Seung-Jung
SJ
Park
Seong-Wook
SW
Huh
Jooryung
J
Wight
Thomas N
TN
Ueno
Hikaru
H
D017130:Angioplasty; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D002404:Catheterization; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics; D003324:Coronary Artery Disease / Q000628:therapy*; D005260:Female; D018014:Gene Transfer Techniques; D006820:Hyaluronic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D058426:Neointima / Q000628:therapy*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015607:Stents / Q000009:adverse effects*; D013552:Swine; D013601:T-Lymphocytes / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
C526316:CCN2 protein, rat; D017252:CD3 Complex; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D006820:Hyaluronic Acid; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D020781:Matrix Metalloproteinase 1