TRANSLATIONAL PHYSIOLOGY
Oxygen free radicals and heart failure: new insight into an old question

Yukitaka Shizukuda and Peter M. Buttrick

Section of Cardiology, University of Illinois at Chicago, Chicago, Illinois 60612


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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-alpha (TNF-alpha ) (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.

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-alpha ) (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.

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.


    ACKNOWLEDGEMENTS

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.


    FOOTNOTES

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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Am J Physiol Lung Cell Mol Physiol 283(2):L237-L238
1040-0605/02 $5.00 Copyright © 2002 the American Physiological Society