Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois 60612
FOR MORE THAN A DECADE, oxygen free
radicals [reactive oxygen species (ROS)] have been proposed as
contributing to the deterioration of cardiac function in patients with
both ischemic and nonischemic cardiomyopathies
(23). There are many reports of enhanced ROS production in diseased myocardium and many plausible sources of ROS,
including mitochondrial dysfunction due to metabolic stress (28), modulation of internal enzyme systems including
NADH/NADPH oxidase (17) and nitric oxide synthase
(16), and local release of inflammatory cytokines such as
of tumor necrosis factor- The study by Hunt et al., the current article in focus (Ref.
9, see p. L239 in this issue),
presents data that suggest a new and novel mechanism by which ROS might
contribute to ventricular dysfunction in human heart disease. They
studied explanted hearts from patients with end-stage heart failure. As
with most studies of this nature, the biological specimens are poorly
characterized, especially with regard to antecedent pharmacotherapy,
and an imperfect group of control hearts is employed. Despite these
limitations, they documented increased activation of a disintegrin and
metalloproteinases (ADAM) in both ischemic and dilated
cardiomyopathic specimens. ADAM is a family of ectoproteases expressed
in cardiac tissue (>30 variants have been described) with structural
homology to snake venom (1, 13, 27) that disrupts
connections between integrins and extracellular matrix (ECM)
components. Although ADAM is known to regulate cell-cell and
cell-matrix interactions in a variety of contexts, its
pathophysiological role in cardiac diseases has not been well
characterized. The finding of Hunt et al. (9) that ROS are
also elevated in these hearts raises the possibility that ROS release
may be a primary or secondary (via increased TNF- The other important observation by Hunt et al. (9) is that
total nitric oxide production is attenuated in end-stage heart failure
and is correlated with increased ROS production. Inhibition of nitric
oxide production by ROS via inhibition of nitric oxide synthase has
been described in other organ systems (16, 26), and the
present study suggests that this inverse relationship may also exist in
end-stage heart failure. Although the number of observations was small,
the ischemic cardiomyopathy group demonstrated less nitric
oxide and more ROS production compared with the nonischemic group. The attenuation of nitric oxide production could potentially make heart failure worse by inducing more endothelial dysfunction, resulting in a metabolic mismatch (14, 21) and further ischemia.
Although the results of this study must be viewed as preliminary,
descriptive, and limited by the fact that they were derived from tissue
that manifested far-advanced disease, they point toward new and
testable hypotheses by which ROS may worsen heart failure. Further
investigation to establish a causal link between ADAM activation and
increased cell death or remodeling using animal models of heart failure
is needed, as are studies aimed at determining the effect of inhibition
of nitric oxide synthase on ROS production in the heart. Unraveling the
molecular moments by which ROS influences cardiac function has proven
to be daunting because of the multiple signaling pathways and potential
cell targets involved (10, 19, 30), but the current study
provides at least a plausible and negotiable road map of investigation
that could lead to novel therapeutic targets.
ARTICLE
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ARTICLE
REFERENCES
(TNF-
) (12) and
interleukins (24) as well as systemic activation of
neurohormonal factors (17, 22). In addition, impaired
vascular reactivity and endothelial dysfunction may contribute
(15, 21). The mechanisms described by which ROS can damage
cardiac muscle are multiple and certainly involve direct toxicity by
inducing both necrosis and apoptosis (5),
impairing myocardial function (3), and inducing cardiac
arrhythmias (2). The impact of increased ROS on cardiac
myocytes is especially pronounced in failing hearts exposed to
hyperglycemia (8), and we have confirmed that the
elevation of ROS in this setting is indeed partially responsible for
apoptosis induced by hyperglycemia in cultured adult cardiac
myocytes (20). In experimental animal models, ROS have
been directly implicated in cardiac injury secondary to anthracycline
exposure (7) and tachycardia (4, 25). Despite
both opportunity and plausible mechanisms, the proof that ROS
materially contribute to progressive cardiac dysfunction in human
disease (as might be evident from the demonstration of salutary effects
of free radical scavengers) is still lacking. This is in part because
the existent pharmacotherapies are imperfect and also because the
signaling pathways proposed to lead to cell apoptosis or
necrosis are complex and redundant and not easily interrupted.
) (18)
mechanism by which ADAM activation occurs. The activation of ADAM with
loss of integrin signaling as a result of detachment from the ECM could
then lead to apoptotic cell death (29) and/or to
cardiac dilatation as a result of matrix disruption. The descriptive
data presented in this study are insufficient to allow an exploration
of causality; however, the hypothesis is plausible and quite consistent
with the data shown. Moreover, there is an accumulating literature
evaluating the role of matrix metalloproteinases in adverse
ventricular remodeling (6, 11) that would seem to support
a role for the ECM-integrin interface in the genesis of this
pathological process.
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ACKNOWLEDGEMENTS |
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The authors acknowledge support from the American Heart Association, Midwest Affiliate (Y. Shizukuda), National Heart, Lung, and Blood Institute Grants HL-62426 and HL-63704 (to P. M. Buttrick), and funds dedicated to the program in cardiovascular sciences at the University of Illinois at Chicago.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. M. Buttrick, Section of Cardiology, Univ. of Illinois at Chicago, M/C 715, 840 S. Wood St., Chicago, IL 60612 (E-mail: buttrick{at}uic.edu).
10.1152/ajplung.00111.2002
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