© 1999 American Heart Association, Inc.
Original Contribution |
Modulation of Cytokine-Induced Cardiac Myocyte Apoptosis by Nitric Oxide, Bak, and Bcl-x
From the Departments of Molecular and Cellular Pharmacology and Medicine (J.Z., K.A.W., N.H.B.), University of Miami School of Medicine, Miami, Fla; Falk Cardiovascular Research Center (D.J.I.), Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif; and Department of Medicine (V.J.D.), Brigham and Women's Hospital, Boston, Mass.
Correspondence to Nanette H. Bishopric, MD, FACC, Associate Professor of Pharmacology and Medicine, Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine (R-189), PO Box 016189, Miami, FL 33101. E-mail nhb{at}chroma.med.miami.edu
Abstract—Cytokine-induced
NO production depresses myocardial
contractility and has been shown to be cytotoxic to
cardiac myocytes. However, the mechanisms of
cytokine-induced cardiac myocyte cell death are unclear. To
analyze these mechanisms in detail, we treated neonatal cardiac
myocytes in serum-free culture with a combination of the
macrophage-derived cytokines interleukin-1ß,
tumor necrosis factor-
, and interferon-
. These cytokines
caused a time-dependent induction of cardiac myocyte apoptosis,
but not necrosis, beginning 72 hours after treatment, as determined by
nuclear morphology, DNA internucleosomal cleavage, and cleavage of
poly(ADP-ribose) polymerase, reflecting caspase activation.
Apoptosis was preceded by a >50-fold induction of inducible NO
synthase mRNA and the release of large amounts (5 to 8 nmol/µg
protein) of NO metabolites (NOx) into the medium. Cell death was
completely blocked by an NO synthase inhibitor and
attenuated by antioxidants (N-acetylcysteine and DTT)
and the caspase inhibitor ZVAD-fmk. Cytokines also
mediated an NO-dependent, sustained increase in myocyte expression of
the Bcl-2 homologs Bak and Bcl-x(L). The NO donor
S-nitrosoglutathione also induced apoptosis and
cell levels of Bak, but not of Bcl-x(L). All effects of
cytokines, including poly(ADP-ribose) polymerase cleavage,
could be attributed to interleukin-1ß; interferon- and tumor
necrosis factor- had no independent effects on apoptosis or
on NOx production. We conclude that cytokine toxicity
to neonatal cardiac myocytes results from the induction of NO and
subsequent activation of apoptosis, at least in part through
the generation of oxygen free radicals. The rate and extent of this
apoptosis is modulated by alterations in the cellular balance
of Bak and Bcl-x(L), which respond differentially to
cytokine-induced and exogenous NO and by the availability
of oxidant species.
Key Words: poly(ADP-ribose) polymerase • protein kinase G • nitric oxide • Bcl-x(L) • oxidative stress
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