on June 3, 2004
Published online before print June 3, 2004, doi: 10.1161/01.ATV.0000134299.89599.53
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Submitted on March 4, 2004
Accepted on May 12, 2004
EGF-Like Domain of Tenascin-C Is Proapoptotic for Cultured Smooth Muscle Cells
Kurt Wallner ;
From the Atherosclerosis Research Center (K.W., C.L., P.K.S., K-J.W., B.G.S.), Division of Cardiology, and Burns and Allen Research Institute, Cedars-Sinai Medical Center, and UCLA School of Medicine, Los Angeles, Calif; and the Department of Pathology (S.M.S.), University of Washington, Seattle.
* To whom correspondence should be addressed. E-mail: Sharifi{at}cshs.org.
Objective--Based on our previous observations on the expression of Tenascin-C (Tn-C) in human atherosclerotic plaques and its colocalization with macrophages, we explored whether Tn-C undergoes fragmentation and the potential pathobiological significance of this fragmentation.
Methods and Results--Using cultured human smooth muscle cells (SMCs), we found that Tn-C upregulates expression of matrix metalloproteinases (MMPs). Western blot analysis revealed that Tn-C substrate is fragmented and most of the cleavage products have fibronectin-like and epidermal growth factor-like (EGF-L) domains of Tn-C. One fragment that contains an EGF-like domain was found in some human atherosclerotic plaques. Cell culture studies revealed that the recombinant EGF-like domain inhibits growth, induces apoptosis of SMCs in a dose-dependent, time-dependent, and caspase-dependent manner, and activates caspase-3 before SMC detachment. Conversely, the caspase inhibitor z-YVAD.cmk, serum, and protease inhibitors blocked cell apoptosis conferred by the EGF-like domain. In addition, these inhibitors blocked EGF-like domain-induced caspase-3 activation. In contrast to this EGF-like domain, intact Tn-C, its fibronectin-like, and its fibrinogen-like domains were inactive.
Conclusions--Together with our previous observations, our data suggest that Tn-C upregulates MMP expression that cleaves Tn-C into fragments containing the EGF-like domain. This domain has proapoptotic activity for SMCs.
Key words: Tenascin-C • metalloproteinases • atherosclerosis • apoptosis • EGF-like domain
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