© 1999 American Heart Association, Inc.
Molecular Medicine |
c-Jun Triggers Apoptosis in Human Vascular Endothelial Cells
From the Division of Biomedical Sciences (N.W., L.V., Y.Z., K.-S.M., M.B.S.), University of California, Riverside, Calif; Chiron Corporation (S.H.), Emeryville, Calif; and Medicine Branch (M.J.B.), National Cancer Institute, National Institutes of Health, Rockville, Md.
Correspondence to Nanping Wang, MD, PhD, Division of Biomedical Sciences, University of California Riverside, Riverside, CA 92521. E-mail nanping.wang{at}ucr.edu
Abstract—In endothelial cells (ECs), the transcription factor c-Jun is induced by a variety of stimuli that perturb EC function. To extend our understanding of the role of c-Jun in EC physiology, we have directed overexpression of c-Jun in human umbilical vein ECs by using a tetracycline-regulated adenoviral expression system. In this study, we report a novel observation using this system. Specific expression of c-Jun is a sufficient trigger for ECs to undergo apoptosis, as demonstrated by a set of combined assays including an ELISA specific for histone-associated DNA fragmentation, DNA laddering, and TdT-mediated dUTP nick end labeling (TUNEL). Tetracycline can effectively shut off c-Jun overexpression and prevent EC apoptosis. Cleavage of poly(ADP-ribose) polymerase was also detected in ECs overexpressing c-Jun. Moreover, inhibitors of cysteine proteases blocked the apoptosis, suggesting a caspase-associated mechanism involved in proapoptotic effects of c-Jun. To gain further insight into the role of c-Jun as a pathophysiological regulator of EC death, TAM67, a dominant-negative mutant of c-Jun, was overexpressed in human umbilical vein ECs to abrogate endogenous c-Jun/activator protein-1 activation. H2O2-triggered apoptosis was largely attenuated in ECs overexpressing TAM67. Together, these results suggest that c-Jun, as a proapoptotic molecule, may play a role in mediating the cell death program in vascular endothelium.
Key Words: c-Jun • adenovirus • endothelial cell • apoptosis • hydrogen peroxide
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