Overexpression of truncated IκBα induces TNF-α-dependent apoptosis in human vascular smooth muscle cells

Hideaki Obara, Atsushi Takayanagi, Junichi Hirahashi, Katsunori Tanaka, Go Wakabayashi, Kenji Matsumoto, Motohide Shimazu, Nobuyoshi Shimizu, Masaki Kitajima

研究成果: Article査読

43 被引用数 (Scopus)


Dysregulation of apoptosis is one of the likely underlying mechanisms of neointimal thickening, a disorder in which proinflammatory cytokines may influence the function of vascular smooth muscle cells (VSMCs) and contribute to atherogenesis. One of these cytokines, tumor necrosis factor-α (TNF-α), induces 2 possibly conflicting pathways, 1 leading to the activation of nuclear factor-κB (NF-κB) and the other leading to caspase-mediated apoptosis. We investigated whether specific inhibition of NF-κB affects TNF-α-dependent apoptosis in human VSMCs. To inhibit NF-κB activation specifically, we constructed a recombinant adenovirus vector expressing a truncated form of the inhibitor protein IκBα (AdexIκBΔN) that lacks the phosphorylation sites essential for activation of NF-κB. The IκBΔN was overexpressed by adenoviral infection and was resistant to stimulus-dependent degradation. Electromobility gel shift and luciferase assays demonstrated that overexpression of IκBΔN inhibited NF-κB activation induced by TNF-α or interleukin-1β (IL-1β). In cells overexpressing IκBAN, TNF-α dramatically induced apoptosis, whereas IL-1β had no effect. The induction was suppressed by treatment with a selective inhibitor of the caspase-3 family, Z-DEVD-fmk, and the overexpression of IκBΔN induced TNF-α-mediated caspase-3 and caspase-2 activity. These results indicate that overexpression of IκBΔN induces TNF-α-dependent apoptosis by efficient and specific suppression of NF-κB and upregulation of caspase-3 and caspase-2 activity in human VSMCs. Our findings suggest that adenovirus-mediated IκBΔN gene transfer may be useful in the treatment of disorders associated with inflammatory conditions, such as the response to vascular injury and atherosclerosis.

ジャーナルArteriosclerosis, Thrombosis, and Vascular Biology
出版ステータスPublished - 2000

ASJC Scopus subject areas

  • 循環器および心血管医学


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