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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:2198.)
© 2000 American Heart Association, Inc.

Vascular Biology

Overexpression of Truncated IB Induces TNF-–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

From the Departments of Surgery (H.O., K.T., G.W., K.M., M.S., M.K.), Molecular Biology (A.T., N.S.), and Internal Medicine (J.H.), Keio University School of Medicine, Tokyo, Japan.

Abstract—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- (TNF-), induces 2 possibly conflicting pathways, 1 leading to the activation of nuclear factor-B (NF-B) and the other leading to caspase-mediated apoptosis. We investigated whether specific inhibition of NF-B affects TNF-–dependent apoptosis in human VSMCs. To inhibit NF-B activation specifically, we constructed a recombinant adenovirus vector expressing a truncated form of the inhibitor protein IB (AdexIBN) that lacks the phosphorylation sites essential for activation of NF-B. The IBN was overexpressed by adenoviral infection and was resistant to stimulus-dependent degradation. Electromobility gel shift and luciferase assays demonstrated that overexpression of IBN inhibited NF-B activation induced by TNF- or interleukin-1ß (IL-1ß). In cells overexpressing IBN, TNF- dramatically induced apoptosis, whereas IL-1ß 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 IBN induced TNF-–mediated caspase-3 and caspase-2 activity. These results indicate that overexpression of IBN induces TNF-–dependent apoptosis by efficient and specific suppression of NF-B and upregulation of caspase-3 and caspase-2 activity in human VSMCs. Our findings suggest that adenovirus-mediated IBN gene transfer may be useful in the treatment of disorders associated with inflammatory conditions, such as the response to vascular injury and atherosclerosis.

Key Words: apoptosis • nuclear factor-B • inhibitory-B • tumor necrosis factor- • vascular smooth muscle cells

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