Journal
CIRCULATION
Volume 105, Issue 5, Pages 633-638Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hc0502.102966
Keywords
restenosis; inflammation; gene therapy; nuclear factor-kappa B; apoptosis
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Background-To investigate the contribution of inflammation to postangioplasty lumen loss, we used an adenoviral gene therapy approach to inhibit the central inflammatory mediator nuclear factor-kappaB (NF-kappaB) by overexpression of its natural inhibitor, IkappaBalpha. Methods and Results-The adenovirus carrying human IkappaBalpha was applied immediately after balloon dilatation by a double-balloon catheter in a rabbit iliac artery restenosis model. Immunohistochemistry of IkappaBalpha revealed that mainly smooth muscle cells of the media but also cells of the adventitia were transduced and expressed the transgene IkappaBalpha for :8 days. At this time point, intercellular adhesion molecule-1 (30%) and monocyte chemotactic protein-1 (50%) expression, as well as recruitment of macrophages into the wounded area (90%), were significantly reduced in IkappaBalpha-treated vessels. In addition, expression of inhibitor of apoptosis proteins was reduced and the percentage of apoptotic cells was increased compared with control-treated contralateral vessels. Animals killed 5 weeks after treatment exhibited a significantly reduced degree of lumen narrowing (P<0.02) on the side treated with adenovirus IκBα. The lumen gain of ≈40% was due to positive remodeling. Conclusions-From these data, we conclude that balloon angioplasty-induced activation of NF-κB contributes to lumen loss likely via induction of an inflammatory response and a decrease in the rate of apoptosis. These data show for the first time that inflammation mediated by NF-κB is involved in postangioplasty lumen narrowing. Specific and more potent inhibitors of NF-κB might therefore be a useful therapeutic measure to improve clinical outcome after balloon dilatation.
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