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Cardiovascular Research 2004 63(1):1-4; doi:10.1016/j.cardiores.2004.04.028
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

The multi-faceted behavior of nitric oxide in vascular "inflammation": catchy terminology or true phenomenon?

Isabella Tritto and Giuseppe Ambrosio*

Division of Cardiology, University of Perugia School of Medicine, Ospedale Silvestrini, via S. Andrea delle Fratte, 06156 Perugia, Italy

*Corresponding author. Tel.: +39-75-527-1509; fax: +39-75-527-1244. Email address: giuseppe.ambrosio{at}ospedale.perugia.it

Received 19 April 2004; accepted 23 April 2004

Abbreviations: NO, nitric oxide • OFRs, oxygen free radicals • ONOO•, peroxynitrite • VSMCs, vascular smooth muscle cells • •O2–, superoxide radical

See article by Hattori et al. [11] (pages 31–40) in this issue.

Over the last 20 years, our understanding of the role of nitric oxide (NO) in biological systems has evolved enormously. Once considered merely a vasodilator (albeit a very powerful one), NO has subsequently attracted attention for its ability to modulate a number of intracellular pathways at the vascular and extravascular level. This is, however, when the headache began. The flurry of studies investigating a variety of possible cellular targets soon led to the discovery that, under different conditions, several pathophysiological events could be affected by NO by seemingly divergent mechanisms.

Initial studies pointed towards a protective effect of NO on cellular activities, indicating that NO would prevent development of the pro-atherogenic phenotype in endothelial cells and vascular smooth muscle cells, reduce leukocyte adhesion and recruitment from the blood stream into the vessel wall, prevent apoptosis, and reduce tissue injury during ischemia–reperfusion [1]. However, it has become evident that the issue is more complicated than this simplified view would predict, since conflicting data have been reported about the effects of nitric oxide on several conditions, such as myocardial contractile function [2], atherosclerosis [3], and ischemia/reperfusion injury [4]. These controversies were only partly explained by differences in experimental models and in the source and amount of NO formed.

Describing the opposite effects of nitric oxide on various aspect of vascular pathophysiology has thus become fuel for an extensive literature centered around the apparently double-faceted nature of this molecule. Accordingly, NO behavior has been at times described as "friend or foe", a "double-edge sword", "yin-yang", or as having a "Janus face". While use of these catchy terms may have undoubtedly helped in simplifying concepts and attracting the attention of the reader, nonetheless it underscores the fact that NO does have a peculiar behavior in biological systems.

With specific regard to possible effects of NO on "inflammatory" events taking place in the vasculature, a major subject of investigation is NF{kappa}B, a transcription factor that plays a fundamental role in orchestrating the cellular response to stress. NF{kappa}B is a family of transcription factors that are considered to be among the major regulators of the functional properties of leukocytes, myocytes, and the vessel wall [5,6]. It is characterized by rapid activation and inhibition, thus allowing a rapid switch of gene expression, and its activation is held to be the central signaling pathway leading to changes in gene expression and cell phenotype in response to various stimuli, including infection, atherogenic stimuli, ischemia and reperfusion [5,6]. The effects of NF{kappa}B in vascular smooth muscle cells (VMSCs) may have important implications since, in addition to their function in structure and vasomotion of the vessels, these cells play a fundamental role during atherogenesis and in the reaction of the vessel wall to balloon injury after PTCA [5]. Proliferation of VSMCs, exposure of adhesion molecules with subsequent leukocyte adhesion, and alteration of extracellular matrix composition are key steps of these processes in which NF{kappa}B activation may represent the central signaling pathway leading to changes in gene expression and cell phenotype [5,6]. The effects of nitric oxide on NF{kappa}B are controversial. While some reports indicate that exposure to NO results in inhibition of NF{kappa}B activation in vascular cells, consistent with its anti-inflammatory properties [7,8], other studies have yielded opposite results, showing paradoxical triggering of NF{kappa}B activation by nitric oxide [9,10].

The paper by Hattori et al. [11], published in this issue of Cardiovascular Research, sheds some light on this issue. The authors exposed VSMCs to LPS, a stimulus for generation of oxygen radicals and activation of NF{kappa}B [12], and studied the effects of exposure to nitric oxide on this phenomenon. Nitric oxide clearly prevented NF{kappa}B activation by LPS, and this effect occurred through inhibition of phosphorylation and subsequent degradation of I{kappa}B-{alpha}, the endogenous inhibitor of NF{kappa}B [11]. This effect was not the consequence of the expected stimulation of guanylate cyclase by NO, since it was independent of cGMP generation. Interestingly, different antioxidants mimicked the inhibitory effect of NO on NF{kappa}B activation in this model [11], consistent with the notion that oxygen radicals are activators of NF{kappa}B [13].

In trying to elucidate the mechanisms of NF{kappa}B inhibition, the authors address some crucial points that need to be kept in mind when studying the effects of nitric oxide and related compounds. In fact, part of the controversy about the effects of nitric oxide in biological systems might be explained by the following points. First, nitric oxide and the oxygen radical superoxide react together with a very high affinity to yield peroxynitrite (ONOO•), which, in itself, is a more stable and powerful oxidant with the ability to induce oxidation and nitration of cellular components; in addition, peroxynitrite may also release NO, partly counteracting the negative effects of oxidative stress [14,15]. Under some pathophysiological conditions, generation of peroxynitrite could actually explain part of the effects directly attributed to nitric oxide [14,16]. Hattori et al. addressed this point by evaluating the effects of direct addition of peroxynitrite, which was not able to prevent the effects of LPS on NF{kappa}B. Secondly, in reacting together, NO and superoxide scavenge each other. The effects of nitric oxide in the paper by Hattori et al. may thus be explained by assuming that LPS activates NF{kappa}B by generating oxygen radicals [12] and that this event may be prevented by scavenging superoxide radical either by the known scavengers tested, or through interaction with NO.

To summarize our current knowledge with an (admittedly) oversimplification, one may speculate that the two-faceted paradigm of NO (or, better still, NO and oxygen radicals) is enriched by a third component. NO and oxygen radicals (OFRs) may exert a variety of effects in their own right (Fig. 1, left panel). In this view, they have been typically considered as being the two sides of a balance: when intracellular conditions tend toward a reduced state, NO generation would prevail and cells remain in a quiescent state, whereas increased formation of oxygen radicals would activate the cellular response to potentially injurious stimuli [17–20]. However, in or near the cells, NO and OFRs may also quickly interact with each other, giving rise to peroxynitrite (ONOO•) (Fig. 1, right panel). This new player is not only endowed with some effects of its own: in fact, as ONOO• formation occurs at the expense of both NO and OFRs, it is likely that cells will be exposed to lower concentrations of both precursors, with consequent changes in the net effects seen [14,17,21].


Figure 1
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  		Fig. 1 Left panel: The two-faceted paradigm of NO and oxygen radicals. Oxygen metabolism, depending on intracellular redox state, pH, and precursor availability, may lead to generation of either NO or superoxide radical (bulletO2–), which may exert a variety of opposite effects in their own right. Prevailing generation of nitric oxide maintains cells in a quiescent state, whereas increased formation of oxygen radicals would activate the cellular response to potentially injurious stimuli and may result in oxidative injury to cells. Right panel: The two-faceted paradigm of NO and oxygen radicals is enriched by a third component. NO and bulletO2– may quickly interact with each other, giving rise to peroxynitrite (ONOObullet), which is endowed with some effects of its own, as it may induce oxidation and nitrosylation of proteins, lipids, and DNA. In addition, it may also release NO, partly restoring nitric oxide concentrations within cells. NO: nitric oxide; bulletO2–: superoxide radical; ONOObullet: peroxynitrite; Plt: platelet. The different thickness of arrows indicates the probability of events to occur.

 
In short, NO may send signals to the cells through at least three different routes: (a) direct effects (NO mediated); (b) secondary effects (following formation of ONOO•); (c) indirect effects (due to diminished OFR concentration). Thus, the body of evidence behind the catchy terminology describing the multi-faceted effects of nitric oxide keeps getting larger and more complex as we investigate it. However, we should not feel overwhelmed by this: rather, it should be a stimulus to further research and a clue to help in our understanding of this fundamental mechanism of cell signaling.


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