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

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.