(Circulation. 1998;98:2883-2890.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Restoration of E2F Expression Rescues Vascular Endothelial Cells From Tumor Necrosis Factor-
–Induced Apoptosis
From the Department of Medicine, Division of Cardiovascular Research, St. Elizabeth's Medical Center, Boston, Mass.
Correspondence to Douglas W. Losordo, MD, Department of Medicine, Division of Cardiovascular Research, St. Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail dlosordo{at}opal.tufts.edu
Background—Normally, quiescent
endothelial cells (EC) line the inner surface of
arteries and protect against thrombosis and neointimal
growth. A variety of noxious stimuli, including balloon angioplasty,
may compromise EC integrity, thereby initiating proliferation and
triggering the local release of cytokines, including tumor
necrosis factor- (TNF-).
Methods and Results—In vivo blockade of TNF- using a soluble
receptor molecule results in accelerated
reendothelialization at sites of balloon angioplasty,
suggesting an important physiological role of
TNF- in attenuating regrowth of endothelium after
balloon angioplasty. Our studies reveal that TNF-, an
apoptosis-inducing cytokine, induces G1 cell-cycle
arrest in proliferating EC. Quiescent EC are relatively immune to
TNF-induced apoptosis versus proliferating EC, which display
repression of the E2F transcription factor coincident with TNF-induced
apoptosis and cell-cycle arrest. We also show that in this
setting, E2F overexpression exerts a survival effect in proliferating
EC and restores cell-cycle progression, in direct contrast to results
of prior reports, which revealed that deregulated expression of E2F in
normally cycling cells induces apoptosis.
Conclusions—These data demonstrate that TNF-induced apoptosis is highly dependent on cell-cycle activity and that E2F can function as survival factor under certain conditions.
Key Words: apoptosis • cells • endothelium • tumor necrosis factor • angioplasty
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