© 1999 American Heart Association, Inc.
Cellular Biology |
Cytokine-Mediated Apoptosis in Cardiac Myocytes
The Role of Inducible Nitric Oxide Synthase Induction and Peroxynitrite Generation
From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.
Abstract—Increased
production of nitric oxide (NO) after induction of the
cytokine-inducible isoform of nitric oxide synthase (iNOS or
NOS2) in cardiac myocytes and other parenchymal cells within the heart
may in addition to contributing to myocyte contractile dysfunction also
contribute to the induction of programmed cell death
(apoptosis). To investigate the mechanism(s) by which increased
NO production leads to apoptosis, we examined the role
of NO in primary cultures of neonatal rat ventricular
myocytes (NRVMs) after induction by the cytokines
interleukin-1ß (IL-1ß) and interferon 
(IFN) or exposure to
the exogenous NO donor
S-nitroso-N-acetylcysteine (SNAC) or
peroxynitrite (ONOO-). Both SNAC (1 mmol/L) and
ONOO- (100 µmol/L), but not their respective
controls (ie, N-acetylcysteine and
pH-inactivated ONOO-), induced
apoptosis in confluent, serum-starved NRVMs at 48 hours.
Similarly, incubation of NRVMs with IL-1ß and IFN for 48 hours
resulted in an increase in iNOS expression, nitrite production,
and programmed cell death. Both the cytokine-induced
nitrite accumulation and myocyte apoptosis could be completely
prevented by the nonselective NOS inhibitor
L-nitroarginine (3 mmol/L) or the specific iNOS
inhibitor
2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT,
100 µmol/L). NO-mediated myocyte apoptosis was not
attenuated by the inhibition of soluble guanylyl cyclase with ODQ, nor
could apoptosis be induced by the incubation of NRVMs with
1 mmol/L 8-bromo-cGMP, a cell-permeant cGMP analogue. However,
NO-mediated apoptosis was significantly attenuated by the
superoxide dismutase mimetic and ONOO- scavenger
Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP, 100 µmol/L).
NO/ONOO--mediated apoptosis was associated with
increased expression of Bax with no change in Bcl-2 mRNA abundance.
Furthermore, apoptotic cell death was also confirmed in adult
rat ventricular myocytes (ARVMs) when grown in
heteroculture with IL-1ß– and IFN-treated rat cardiac
microvascular endothelial cells. Therefore,
cytokine-induced apoptosis in NRVMs and ARVMs is
mediated by iNOS induction, ONOO-, and associated with an
increase in Bax levels.
Key Words: nitric oxide • peroxynitrite • cytotoxicity • apoptosis • programmed cell death
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