Korean Circ J.  2004 Jan;34(1):59-68. 10.4070/kcj.2004.34.1.59.

Blockade of TGF-beta by Catheter-based Gene Transfer of a Soluble TGF-beta Type II Receptor Inhibits Neointima Formed after Stenting

• Chung IM
• Choi DH
• Min PK
• Chung KY

• KMID: 1938855
• DOI: http://doi.org/10.4070/kcj.2004.34.1.59

Abstract

BACKGROUND
Enhanced extracellular matrix (ECM) accumulation is an important finding in coronary stent restenotic tissue, in which TGF-beta, implicated in ECM formation, is expressed abundantly. We assessed the hypothesis that blockade of TGF-beta by the local delivery of an adenovirus expressing a soluble form of the TGF-beta type II receptor (AdT beta-ExR), inhibits stent-induced neointima in porcine coronary arteries.
METHODS
Two remote coronary arterial segments (n=20) per pig randomly received 1x10(9) pfu of either AdT beta-ExR or adenovirus expressing beta-galactosidase (AdLacZ)/PBS, using an Infiltrator(TM). Stents (n=20) were deployed, after gene transfer, in each segment of 10 pigs. Localized transgene expression was confirmed by both reverse transcription-PCR and immunohistochemistry. Computer-based morphometric assessment was performed in the stented arteries 4 weeks after the gene transfer.
RESULTS
There was significantly less intimal area (1.57+/-0.49 vs. 2.13+/-0.34 mm2), area ratio of intima/media (0.84+/-0.44 vs. 1.32+/-0.48) and higher neointimal cell density (3121+/-330 vs. 2812+/-183 cells/mm2) in the arteries treated with AdT beta-ExR compared to the controls (all, p<0.05). Neither the cell proliferation rate, assessed by PCNA immunohistochemistry, nor the injury score were significantly different between the two groups. The distribution of hyaluronan in the intima was less in 4 of the 6 AdT beta-ExR treated arteries compared to the controls.
CONCLUSION
Blockade of TGF-beta, by a local in vivo gene transfer of a soluble TGF-beta receptor, inhibits stent-induced neointima, probably by inhibiting the ECM accumulation in porcine coronary arteries, which may have therapeutic potential in the inhibition of restenosis after stenting.

Keyword

Extracellular matrix; TGF-beta; Stents; Coronary restenosis; Gene therapy

MeSH Terms

Adenoviridae
Arteries
beta-Galactosidase
Cell Count
Cell Proliferation
Coronary Restenosis
Coronary Vessels
Extracellular Matrix
Genetic Therapy
Hyaluronic Acid
Immunohistochemistry
Neointima*
Proliferating Cell Nuclear Antigen
Receptors, Transforming Growth Factor beta
Stents*
Swine
Transforming Growth Factor beta*
Transgenes
Hyaluronic Acid
Proliferating Cell Nuclear Antigen
Receptors, Transforming Growth Factor beta
Transforming Growth Factor beta
beta-Galactosidase