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

Ick Mo Chung, Junwoo Kim, Youngmi K. Pak, Yangsoo Jang, Woo Ick Yang, Innoc Han, Seung Jung Park, Seong Wook Park, Jooryung Huh, Thomas N. Wight, Hikaru Ueno

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 TM , 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.

Original languageEnglish
Pages (from-to)468-475
Number of pages8
JournalInternational Journal of Cardiology
Volume145
Issue number3
DOIs
Publication statusPublished - 2010 Dec 3

Fingerprint

Transforming Growth Factors
Stents
Coronary Vessels
Swine
Catheters
Inflammation
Genes
Extracellular Matrix
Adenoviridae
Galactosidases
Connective Tissue Growth Factor
Neointima
Adventitia
Matrix Metalloproteinase 1
Growth Factor Receptors
Hyaluronic Acid
Reverse Transcription
Smooth Muscle Myocytes
Blood Vessels
Pathologic Constriction

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

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. / 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. In: International Journal of Cardiology. 2010 ; Vol. 145, No. 3. pp. 468-475.
@article{cc3afebee3604d3594681387f76701e4,
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 TM , 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.",
author = "Chung, {Ick Mo} and Junwoo Kim and Pak, {Youngmi K.} and Yangsoo Jang and Yang, {Woo Ick} and Innoc Han and Park, {Seung Jung} and Park, {Seong Wook} and Jooryung Huh and Wight, {Thomas N.} and Hikaru Ueno",
year = "2010",
month = "12",
day = "3",
doi = "10.1016/j.ijcard.2009.11.032",
language = "English",
volume = "145",
pages = "468--475",
journal = "International Journal of Cardiology",
issn = "0167-5273",
publisher = "Elsevier Ireland Ltd",
number = "3",

}

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. / 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.

In: International Journal of Cardiology, Vol. 145, No. 3, 03.12.2010, p. 468-475.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Chung, Ick Mo

AU - Kim, Junwoo

AU - Pak, Youngmi K.

AU - Jang, Yangsoo

AU - Yang, Woo Ick

AU - Han, Innoc

AU - Park, Seung Jung

AU - Park, Seong Wook

AU - Huh, Jooryung

AU - Wight, Thomas N.

AU - Ueno, Hikaru

PY - 2010/12/3

Y1 - 2010/12/3

N2 - 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 TM , 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.

AB - 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 TM , 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.

UR - http://www.scopus.com/inward/record.url?scp=78149349800&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78149349800&partnerID=8YFLogxK

U2 - 10.1016/j.ijcard.2009.11.032

DO - 10.1016/j.ijcard.2009.11.032

M3 - Article

C2 - 20053468

AN - SCOPUS:78149349800

VL - 145

SP - 468

EP - 475

JO - International Journal of Cardiology

JF - International Journal of Cardiology

SN - 0167-5273

IS - 3

ER -