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(Circulation Research. 2006;98:1490.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Integrin-Mediated Transcriptional Activation of Inhibitor of Apoptosis Proteins Protects Smooth Muscle Cells Against Apoptosis Induced by Degraded Collagen

Karin von Wnuck Lipinski, Petra Keul, Nicola Ferri, Susann Lucke, Gerd Heusch, Jens W. Fischer, Bodo Levkau

From the Institute of Pathophysiology (K.v.W.L., P.K., S.L., G.H., B.L.), Center of Internal Medicine, University Hospital, Essen, Germany; Department of Pharmacological Sciences (N.F.), University of Milan, Italy; and Molecular Pharmacology (J.W.F.), Institute of Pharmacology and Clinical Pharmacology, Heinrich-Heine University Düsseldorf, Germany.

Correspondence to Bodo Levkau, Institute of Pathophysiology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany. E-mail levkau{at}uni-essen.de

Apoptosis of smooth muscle cells (SMC) and degradation of the extracellular matrix (ECM) have both been implicated in atherosclerotic plaque rupture. We have previously reported that degraded type I collagen fragments induce a rapid but transient apoptotic burst initiated by calpains in SMC. The aim of the current study was to identify the pathway responsible for consecutive SMC survival. We show that exposure of SMC to collagen fragments resulted in a sustained activation of nuclear factor (NF)-B via phosphorylation and degradation of IB. Its prevention through retroviral expression of superrepressor IB or proteasome inhibition potently induced apoptosis. In the presence of blocking antibodies to _vß₃ integrin and RGD peptides, collagen fragments no longer activated NF-B and apoptosis was enhanced. The mechanism by which NF-B was protecting SMC against collagen fragment-induced apoptosis was a transcriptional activation of several endogenous caspase inhibitors of the inhibitor of apoptosis protein (IAP) family as: (1) the expression of xIAP, c-IAP2, and survivin was potently induced by collagen fragments; (2) IAP expression was abrogated by superrepressor IB; and (3) knockdown of each of the 3 IAPs by small interfering RNA (siRNA) resulted in enhanced apoptosis after collagen fragment treatment. Our data suggest that SMC exposed to degraded collagen are protected against apoptosis by a mechanism involving _vß₃-dependent NF-B activation with consequent activation of IAPs. This may constitute a novel antiapoptotic pathway ensuring SMC survival in settings of enhanced ECM degradation such as cell migration, vascular remodeling, and atherosclerotic plaque rupture.

Key Words: apoptosis • caspase activation • NF-B • vascular smooth muscle cells • collagen • extracellular matrix • atherosclerosis

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