© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Cytokine-induced free radicals and their roles in myocardial dysfunctions
aMRCC Group in Immuno–Cardiovascular Interaction, Department of Anatomy and Cell Biology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4
bDepartment of Pharmacology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Québec, Canada, J1H 5N4
gbkail01{at}courrier.usherb.ca
* Corresponding author
Received 22 January 1999; accepted 2 February 1999
See article of Cheng et al. [9] (pages 651–659) in this issue.
Recent studies dealing with oxygen free radicals and nitric oxide (NO) have demonstrated their implications in diseases such as inflammation, ischemia–reperfusion injury and several other cardiovascular dysfunctions [1–4].
Activated oxygen species, such as singlet oxygen, superoxide anion (O2–), hydrogen peroxide (H2O2) and hydroxyl radical (OH–) are highly unstable, extremely reactive and highly toxic [4]. Superoxide anions are usually required for the generation of H2O2 and OH–. The generation of free radicals is a normal physiological phenomenon, which is controlled by naturally occurring scavengers produced by the cell such as superoxide dismutase (SOD), glutathione peroxidase (GSHPx), catalase and non-enzymatic antioxidants such as vitamins E and C. However, the main pathological effects of free radicals generation are correlated, in the short-term with their accumulation within the cells and in the long-term, with a reduction in the production of the cells natural scavengers. Consequently those events will promote the sustained accumulation and toxicity characteristics of those free radicals.
Free radicals are generated in several cardiac diseases and their cellular accumulation during coronary occlusion and reperfusion in several animal models, including dogs, may contribute to ischemia reperfusion-induced injury [4]. However, several other mechanisms and mediators may be involved in heart injury at different stages, from blood stasis to the reperfusion period. Among these products of heart injury, circulating AngII and NO were reported to be increased [3,5]. Data in the literature also confirm that there is an intimate cross-talk between NO overproduction and free radical overformation in the injured heart. It seems that the product of NO and superoxide anion, peroxynitrite (ONOO–), could be the element contributing to the development of cardiovascular dysfunction [6]. Amazingly, in several animal models, improved hemodynamic function were reported after treatment with free radicals scavengers, antioxidant vitamins, NO inhibitors or ACE inhibitors [5,7,8]. It seems that one of main sources of free radicals is activated neutrophils, which by their infiltration into the injured cardiac zone, contribute to free radical dependent pathogenesis of heart diseases in several species including man. The study by Cheng et al. [9] in this issue provides first hand evidence that intra-coronary administration of microspheres coated with interleukin-1β induced neutrophil infiltration, increased superoxide production and decreased left ventricular ejection fraction (LVEF) in the dog model. One important finding of this report is that, for the first time, it was shown that pretreatment with a non-scavenger inhibitor of superoxide production (OPC-6535) prevented the IL-1β-induced myocardial dysfunction in the dog without affecting neurophil infiltration [9]. Cheng et al. [9] also showed that OPC-6535 blocked the formation of peroxynitrite from superoxide anions and nitric oxide. There is no doubt that the results reported by the authors add an important new element to the role of free radicals in myocardial dysfunction and the possible beneficial effect of a new inhibitor of superoxide anion production.
However, a pivotal element of the present study lies in the cardioprotective characteristics of systemically administered OPC-6535. One would question the effect of superoxide anions inhibition on several circulating hormones and neuro-humoral factors. Hence, this would suggest that OPC-6535 affects not only heart muscle contractility but also the vascular system and more specifically the endothelial integrity which influences per se the overall cardiac function. For example, it was recently suggested that development of endothelial dysfunction is linked to an overproduction of nitric oxide synthase (NOS) and O2– to consequently enhance the formation of peroxynitrite [6]. Thus, peroxynitrite is not only produced by activated neutrophils but also could be produced by neutrophil–endothelial cells interaction via a direct physical contact and/or indirectly via activated immune cells-released factors such as PAF, TNF-
and IL-1β [10]. Another key player in the free radical mediated heart injury is peroxidation of membrane phospholipids which may highly modify plasma membrane permeabilities as well as contribute to the overstimulation of prostaglandins synthesis, the release of which, will in turn contribute to the overproduction of oxygen free radicals. Thus, it is difficult, using in vivo and even in vitro studies, to conclude that free radicals and mainly superoxide overproduction are the key players in IL-1β or any cytokines and circulating hormones-induced heart injuries. Several interesting questions can be raised from the work of Cheng et al. [9] in this issue: (1) Why the inhibitor did not affect the basal superoxide production, if any? (2) If β-receptors blockade, ACE inhibitors, NO inhibitors and superoxide anion inhibitor had beneficial effects on free radicals-induced heart dysfunction, which of these inhibitors could be a safe therapeutic drug in humans? (3) Does the inhibitor of superoxide prevent long-term free radical cytotoxicity and would this agent be efficient in therapy? (4) Is the formation of peroxynitrite really the only product responsible of the observed IL-1β-induced myocardial dysfunction? Indeed, peroxynitrite may enhance the toxicity of NO and O2– induced cardiac dysfunction [11].
Other cytokines such as TNF- have been shown to induce marked coronary constriction through the release of endogeneous ET-1 [12]. In addition IL-1β is a well-known inducer of several other proinflammatory enzymes such as the inducible COX-2.
Another important question that should be raised, is that if NO and O2– overproduction is a normal phenomenon that occurs in response to injury through the activation of the immune cells, will the blockade of these two systems, which certainly protects the myocardial tissues from pathogens, jeopardize the integrity of the normal immune response?
It is essential to point out that the endocardial and vascular endothelium are relatively unaffected by their own constitutively produced NO (i.e. no negative influence on Ca2+-dependent mechanisms). Only when peroxynitrites are formed, through i-NOS activity, are the endothelial intracellular Ca2+ pools depleted [13]. This would suggest that superoxide anions should not be inhibited in conditions of constitutively produced NO, as found in the non-infarcted regions of the myocardium.
It is also of interest that the authors [9] pinpoint i-NOS as the main culprit of the cytokine-induced myocardial dysfunction, through the use of aminoguanidine.
However, the latter compound is less than selective for i-NOS since it affects neuronal NOS, diamine oxidase and ribonucleotide reductase as well [14]. More selective inhibitors such as 3-aminomethylbenzyl acetamidine (1400 W) would have been preferable to definitely identify a role for i-NOS in the present experimental model.
Finally, it would have been interesting to prevent neutrophil infiltration in the myocardium through the use of specific neutrophil antibodies and correlate that inhibition with an improved cardiac function (i.e. is there necessarily a cell–cell contact?).
Thus, the role of free radicals in general and superoxide anion in heart dysfunction remains an open field due to the increasing number of key players implicated in the generation of superoxide anion and the dependency of the later on NO production in order to form peroxynitrite. There is, however no doubt that specific inhibitors of superoxide anion will provide important pharmacological tools in the field and that their efficiency in man has to be validated.
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