title: 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 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.
authors.affiliation: 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
authors.forename: Ick-Mo
authors.initials: IM
authors.lastname: Chung
authors.forename: Junwoo
authors.initials: J
authors.lastname: Kim
authors.forename: Youngmi K
authors.initials: YK
authors.lastname: Pak
authors.forename: Yangsoo
authors.initials: Y
authors.lastname: Jang
authors.forename: Woo-Ick
authors.initials: WI
authors.lastname: Yang
authors.forename: Innoc
authors.initials: I
authors.lastname: Han
authors.forename: Seung-Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Seong-Wook
authors.initials: SW
authors.lastname: Park
authors.forename: Jooryung
authors.initials: J
authors.lastname: Huh
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ueno
mesh_terms: 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*
chemical_list: 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