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Cardiovascular Research 2006 69(2):309-317; doi:10.1016/j.cardiores.2005.10.010
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Copyright © 2005, European Society of Cardiology

On the impact of NO–globin interactions in the cardiovascular system

Axel Gödecke*

Institut für Herz-und Kreislaufphysiologie, Heinrich-Heine Universität Postfach 101007, 40001 Düsseldorf, Germany

* Tel.: +49 211 8112675; fax: +49 211 8112672. Email address: Axel.Goedecke{at}uni-duesseldorf.de

Received 22 July 2005; revised 11 October 2005; accepted 24 October 2005


   Abstract
Top
 Abstract
1. Introduction
 2. The globin family...
 3. NO-hemoglobin interactions in...
 4. NO-myoglobin interactions in...
 5. Myoglobin scavenger and...
 6. Summary
 References
 
During the last years, many reports have provided evidence that the concept of a simple, diffusion-controlled action of NO must be extended by the existence of storage and long-distance transport forms of NO suitable to extend the half-life of the NO radical. In addition, hemoglobin (myoglobin)-dependent formation of NO may account for an additional NO source in the vasculature and in red muscle. On the other hand, there is increasing evidence that the specific subcellular localization of NO synthase isoforms is a critical determinant for their proper biological function. However, it remains obscure how a localized mode of NO action may occur without effective barriers that prevent the diffusion of NO released at a specific site within a cell to other compartments. Members of the globin family of proteins, mainly hemoglobin and myoglobin, have been found to play important roles in all of these processes.

KEYWORDS Nitric oxide; Myoglobin; S-nitrosation


   1. Introduction
Top
 Abstract
 1. Introduction
2. The globin family...
 3. NO-hemoglobin interactions in...
 4. NO-myoglobin interactions in...
 5. Myoglobin scavenger and...
 6. Summary
 References
 
Without any doubt nitric oxide is one of the major regulatory factors involved in modulation of many cellular functions throughout most organs and cell types. In the cardiovascular system this gaseous transmitter is involved in control of blood pressure [1], cardiac contractile force, Ca2+ homeostasis and energetics [2], but it also influences growth and differentiation processes such as smooth muscle cell proliferation [3] and angiogenesis either by direct action on resident cells [4,5] or by influencing the attraction of circulating progenitor cells to sites of injury [6].

NO is formed enzymatically by the action of three well characterized NO synthases which oxidize the guanidino group of L-arginine to form NO [7]. Once formed, the free radical gas NO may exert biological functions within the cell of origin but may also travel across cell borders to modulate biological functions in adjacent cells. On its diffusion path the highly reactive NO radical may react with many different molecules including oxygen, superoxide anions, thiol-groups of proteins, and may bind to prosthetic heme groups in many heme proteins or to binucleate centers of cytochrome c oxidase of the respiratory chain [8]. The complex chemistry of NO makes it hard to predict the functional consequences as the mentioned interactions may stimulate or inhibit the targeted molecules or even may be without any functional alteration. These considerations imply that the biological activity of NO released from a cell may be limited by its decrease in concentration due to radial diffusion but also from the relative composition of NO binding partners in the environment. Therefore, it is not surprising that estimations of the effective radius of NO action vary between a few 100 nm to several micrometers.

A well established mechanism of NO-mediated signal transduction is the activation of soluble guanylyl cyclase (sGC) which is expressed in many cell types as a heterodimeric heme protein (see [9] for review). Upon sGC activation, intracellular cGMP levels are raised. cGMP then may modulate the function of downstream targets such as cGMP-dependent protein kinases, phosphodiesterases or ion channels.


   2. The globin family of proteins
Top
 Abstract
 1. Introduction
 2. The globin family...
3. NO-hemoglobin interactions in...
 4. NO-myoglobin interactions in...
 5. Myoglobin scavenger and...
 6. Summary
 References
 
The globin family of proteins is composed of a large number of members which are expressed in bacteria, protozoa, plants and animals. Globins are characterized by a specific tertiary structure, the globin-fold, which is comprised of eight {alpha}-helices wrapped around a prosthetic heme group which contains a central ferrous iron. The typical globin structure is well known since the pioneering work of Max Perutz and John Kendrew on the most abundant vertebrate globins, hemoglobin and myoglobin [10,11]. Meanwhile, a large number of proteins with a globin like structure exerting many specialized functions have been identified in almost all organisms including bacteria, fungi, plants, invertebrates and vertebrates [12]. All of these proteins retain the principal globin structure. However, dimeric globins and also truncated globins with a reduced number of helices have been found [13]. Flavohemoglobins contain in addition to the globin domain an NADH/FADH binding site and represent in bacteria and yeast yet another type of globins [14]. In addition, the so-called globin coupled sensors (GCS) which are in part involved in bacterial aerotaxis show a modular structure: a N-terminal sensing globin domain is fused to a C-terminal signal transduction domain with properties of guanylyl cyclases and phosphodiesterases [15].

Recently, two new members of the globin family, named neuroglobin and cytoglobin, have been discovered to occur in vertebrates besides the well known hemoglobin and myoglobin [16,17]. As implied by its name, neuroglobin was found to be expressed predominantly in neuronal cell types with high levels in retinal cells [18]. In contrast, cytoglobin expression was found in many cell types and it appears to be localized within the nucleus [19]. The precise role of these "new globins," however, remains to be deciphered.

A common feature of the globins analysed so far represents the reversible binding of oxygen to the heme-bound iron. Obviously, hemoglobin and myoglobin are involved in oxygen transport in the blood and oxygen storage in muscle cells, respectively. In addition, evidence has accumulated that these proteins may exert additional, enzyme-like functions as outlined below.


   3. NO–hemoglobin interactions in the vascular system
Top
 Abstract
 1. Introduction
 2. The globin family...
 3. NO-hemoglobin interactions in...
4. NO-myoglobin interactions in...
 5. Myoglobin scavenger and...
 6. Summary
 References
 
Nitric oxide released from the vascular endothelium is a major regulator in the control of blood pressure and organ perfusion. This effect is mediated by the NO dependent stimulation of sGC in vascular smooth muscle cells leading to vasorelaxation. Besides agonists such as bradykinin and ATP, mechanical forces of the blood stream acting on endothelial cells represent a major determinant of the NO levels released from the endothelium. Both activation of endothelial NO synthase activity and elevated eNOS expression are involved in this process. The phenomenon of flow mediated vasodilation, which is of clinical value for the examination of endothelial dysfunction, depends to a large extent on NO as the major mediator [20].

Already in the early days of nitric oxide research, free oxy-hemoglobin and oxy-myoglobin were used to inactivate NO released from cells to scavenge NO and thereby to provide evidence of NO mediated processes [21]. The basis for this application is the dioxygenation reaction NO+Hb(Mb):O2->met-Hb(Mb)+NO3Formula which also underlies the oxy-hemoglobin assay for the detection of NO [22]. While it has experimental value, this reaction is also responsible for the disappointing outcomes of clinical trials with free hemoglobins as blood-substitutes. Extracellular Hb:O2 effectively destroys NO, which leads to pronounced hypertension [23]. This finding raises the question why oxy-hemoglobin, which is present in the blood in vast excess, does not lead to a similar extent of destruction of bioactive NO. Modelling of the diffusion path of NO from the vascular endothelium into the erythrocyte demonstrated that multiple diffusion barriers such as unstirred layers around erythrocytes and the vascular endothelium limit NO diffusion to erythrocytes and across the erythrocyte membrane [24,25]. Thus, the intracellular hemoglobin trapped inside of erythrocytes is 500–1000 fold less effective in NO degradation as the same concentration of free hemoglobin.

The paradigm of a sole role of NO destruction by hemoglobin was challenged by the SNO–hemoglobin theory [26–28]. According to this model Stamler and coworkers postulated that NO might cooperatively react with deoxygenated hemoglobin allowing the formation of nitrosyl-(FeII)–hemoglobin. The heme-bound NO is then transferred to the thiol group of Cys93 of hemoglobins β-subunit forming S-nitrosated hemoglobin. Upon allosteric transition from the R- to the T-state, which occurs when hemoglobin is deoxygenated, the bound NO should be released from the cystein and might induce vasodilation. Thus, this mechanism suggests a role for hemoglobin in NO storage and long distance transport. It therefore implies an endocrine mode of NO action which would induce vasodilation at sites of low oxygen tension thereby enhancing local flow and tissue oxygenation. This mechanism may therefore have important clinical implications. Indeed, measurements of the AV differences for NO metabolites revealed that in patients with congestive heart failure but not in normal control individuals substantial gradients for nitrosyl–hemoglobin and SNO–hemoglobin in accordance with the SNO–hemoglobin theory existed. Thus, under conditions of elevated peripheral oxygen extraction an elevated NO release from the storage form SNO–hemoglobin may support tissue oxygenation [29]. However, this attractive concept has been doubted by many groups because key features of the SNO–hemoglobin theory such as the cooperative binding of NO to deoxy-hemoglobin [30] or the transition of NO from the iron nitrosyl complex to the thiol of Cys93 [31] could not be reproduced. In summary, the concept of an SNO–hemoglobin mediated paracrine mode of NO action is still under intense debate [32,33].

Despite all controversies about the role of hemoglobin as NO store and transporter the observation remains that both inhaled NO gas or authentic NO solution are able to dilate vessels at remote sites [34,35]. This effect may be mediated in part by S-nitrosothiols [36]. However, under hypoxic conditions recent data suggest that NO which is derived from nitrite by the nitrite reductase activity of hemoglobin may account for the observed vasodilatory effects [37,38].

Nitrite is found in 300–500 nM concentrations in plasma [39] and even higher values have been detected in tissues. It has been proposed that nitrite reflects to a large extent the activity of the endothelial NO synthase and is formed most likely according to the equation 2 NO+O2->2NO2Formula.

Nitrite might represent an NO storage pool [33] because hemoglobin, at least in a deoxygenated state, is able to reduce nitrite with the formation of NO. Already in 1981, Doyle and coworkers described that the reaction of nitrite with deoxy-hemoglobin may yield NO [40] which associates with deoxy-hemoglobin to form nitrosyl–hemoglobin. In view of a biological function of this reaction it must be noted that in the presence of deoxygenated erythrocytes NO2Formula in near physiological concentrations (500 nM) is able to relax rat aortic rings [41]. Moreover, nitrite itself has been demonstrated to relax the human vasculature, an effect which is more pronounced under hypoxic conditions. Thus, it appears that hemoglobin may act as a PO2-regulated nitrite reductase, which generates NO from its storage form nitrite [37,38] and thus might support local organ perfusion under hypoxic conditions.


   4. NO–myoglobin interactions in the heart
Top
 Abstract
 1. Introduction
 2. The globin family...
 3. NO-hemoglobin interactions in...
 4. NO-myoglobin interactions in...
5. Myoglobin scavenger and...
 6. Summary
 References
 
Myoglobin is a monomeric oxygen-binding heme protein which structurally resembles a monomeric subunit of the hemoglobin tetramer. It is highly expressed in type I and IIa skeletal muscle fibers and in cardiac muscle, i.e. in those muscle types prone to perform sustained work. In contrast to the clear situation in cardiac and skeletal muscle, little is known about the expression of myoglobin in smooth muscle cells. Whereas it has long been assumed that myoglobin is absent from smooth muscle a few reports have demonstrated the presence of myoglobin in smooth muscle from bladder, small intestine and uterus [42]. In contrast to striated and cardiac muscle, myoglobin expression occurs at a much lower level in these cell types.

Myoglobin in muscle serves predominantly as an intracellular store for oxygen able to buffer short phases of ischemia, which periodically occur in the heart during the systolic compression of the coronary circulation [43]. In addition, myoglobin is (arguably) discussed to facilitate oxygen diffusion within muscle cells, i.e. besides a flux of physically dissolved oxygen, a flux of myoglobin-bound oxygen may occur from the capillary to the mitochondria [44,45]. Although studied quite intensively there is still no consensus on this function. In the last years the investigation of myoglobin's functions in vivo has been stimulated with the generation of myoglobin knockout mice by two laboratories [46,47]. These mice which lack myoglobin throughout the body, are characterized by a benign phenotype due to the activation of multiple compensatory mechanisms which to a large extent preserve the oxygen-related functions of myoglobin. These include increased capillary density, elevated Hb in the blood, increased coronary flow and a switch in cardiac substrate utilization from "oxygen poor" fatty acid to the "oxygen rich" glucose [48]. This adaptation is so powerful that myoglobin knockout mice tolerate hypoxic conditions to a similar extent as wild type mice [49]. Thus, all of these mechanisms contribute to compensation for the loss of the oxygen-storage and -transport protein myoglobin.

Basically, the same NO-related chemistry which applies to hemoglobin is also found for myoglobin (Fig. 1). Early in vitro experiments revealed that myoglobin, as its relative hemoglobin, is able to perform dioxygenation of NO. This reaction primarily leads to generation of peroxynitrite as a short lived intermediate which isomerises to nitrate before leaving the O2 binding pocket of myoglobin [50]. In analogy to the SNO–hemoglobin theory it has also been suggested that at least human myoglobin may bind and conserve NO via S-nitrosation [51,52]. This reaction is supposed to occur at Cys110 which is found in human myoglobin but not in myoglobin of many other species. It is assumed to fulfil a similar function as Cys93 of the hemoglobin β-subunit. Ex vivo, SNO–myoglobin was able to dilate vessel segments via NO release. To which extent SNO–myoglobin may be formed and functionally relevant in vivo remains to be seen.


Figure 1
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  		Fig. 1 Summary of the proposed functions of myoglobin:NO interactions in cardiac myocytes. On the left reactions involved in formation/conservation of NO (nitrite reductase activity) and SNO–myoglobin formation are shown which may occur under hypoxic conditions. On the right reactions involved in NO degradation are listed (NO dioxygenase function). This reaction attenuates the general effect of NO in cardiac myocytes. It may also play a role in the generation of subcellular compartments and protect the respiratory chain from NO-mediated inhibition. Myoglobin is schematically shown with its heme-bound iron. (SL: sarcolemma, SR: sarcoplasmic reticulum, MIT: mitochondria, CF: contractile filaments).

 
As hemoglobin, myoglobin possesses a nitrite reductase activity. The typical red colour of cured meat is the result of NO formation due to reaction of nitrite with deoxy-myoglobin and the subsequent formation of nitrosyl–myoglobin complexes (Fig. 1). It can be speculated that nitrite reduction may occur in the ischemic heart in vivo as well. Indeed, it was recently shown that in the ischemic heart nitrite derived nitrosyl–myoglobin complexes are formed [53]. Because the reaction leading to the NOS-independent formation of NO from nitrite was not identified in that study, it will be interesting to see whether myoglobin is involved in this process. Several studies have addressed the role of NO in ischemia–reperfusion and found NO to be cardioprotective [54,55]. Thus, myoglobin dependent formation of nitrite-derived NO may contribute to these beneficial effects. These few examples show, that myoglobin's functions may not be restricted to oxygen storage and intracellular transport. Rather it might represent a critical modulator of NO functions in cardiac and skeletal muscle.


   5. Myoglobin scavenger and barrier for NO in the heart
Top
 Abstract
 1. Introduction
 2. The globin family...
 3. NO-hemoglobin interactions in...
 4. NO-myoglobin interactions in...
 5. Myoglobin scavenger and...
6. Summary
 References
 
As pointed out above the enclosure of hemoglobin within the erythrocyte abolishes the mass destruction of vascular NO and enables the biological functions of NO signalling in the vascular system. However, as little as 4 µM of free oxy-hemoglobin were found to induce the same extent of vasoconstriction as red blood cells at a hematocrit at 30% [56,57]. As the rate constant for dioxygenation of NO by oxy-hemoglobin and oxy-myoglobin are quite similar, it seems likely that NO function in the heart must be substantially influenced by myoglobin, because cardiac expression levels of myoglobin range from 200 µM to 2 mM in different species. Furthermore, NO synthase and myoglobin expression occur without spatial separation side by side within the same cell.

The modulation of cardiac function by NO has been the subject of many reviews ([2,58] and references therein) and therefore only a few aspects, which appear important for the topic of this review, will be briefly summarized. Within the heart all three NOS isoforms, endothelial, neuronal, and inducible NOS are expressed, but the extent of expression may be modulated under different (patho)physiological conditions [59]. Whereas eNOS and nNOS are generally considered to be expressed constitutively, the majority of reports assumes that relevant expression of iNOS occurs only under pathological conditions such as dilated cardiomyopathy and myocarditis [60,61].

A large number of cardiac effects, such as modulation of basal and catecholamine-stimulated contractility, transduction of the parasympathetic effects of cholinergic stimulation, attenuation of oxygen consumption, and cardiomyocyte apoptosis have been ascribed to NO. However, not all of these effects are generally accepted [62–73]. Despite some dissent, the diverse functions of NO in the heart have raised the question which NO sources might be involved.

eNOS is the major NOS isoform in the heart which is predominantly expressed in the coronary and endocardial endothelium. In addition, eNOS was found in the specialized cardiomyocytes of the sinoatrial and atrioventricular nodes and within cardiac myocytes [74]. Thus, in the heart eNOS may affect contractile function in an autocrine and paracrine manner. The neuronal NOS is quantitatively less expressed within the heart and this isoform was first described in cardiac nerves and the conduction system. It is now commonly accepted that nNOS may also be expressed in cardiac myocytes. Both, eNOS and nNOS may modulate chronotropy of the heart. nNOS appears to facilitate predominantly the presynaptic release of acetylcholine and thereby to enhance the negative chronotropic effect of parasympathetic stimulation. For eNOS a dual mode of action has been described. Whereas the NO–cGMP mediated inhibition of ICaL in SA nodal cells may reduce heart rate, it has also been demonstrated that low doses of NO may stimulate the hyperpolarisation induced If current in these cells which might elevate heart rate. Thus, the net effect of eNOS on heart rate may depend on the degree of eNOS stimulation and secondary factors such as the level of sympathetic tone (for review see Paterson, [75]).

A common feature of eNOS and nNOS which are coexpressed within cardiac myocytes is their highly defined spatial organization. eNOS appears to be localized predominantly at the sarcolemmal membrane and was found to reside in caveolae, specialized microdomains at which many signal transduction pathways pass the cell membrane [76,77]. Here this isoform forms protein–protein interactions with caveolin-3, the major scaffolding protein of muscle membrane caveolae. Interestingly, enzymes, which recycle the NOS substrate L-arginine from L-citrulline, are also localized in caveolae, which might be important to ensure substrate supplies for eNOS [78–80]. In contrast, nNOS associates with the SR and complex formation with the ryanodine channel has been observed [81]. This spatial confinement led to the assumption that both NOS isoforms in cardiac myocytes may exert different functions in the heart.

It has been clearly shown that eNOS derived NO is able to reduce the inotropic response to β-adrenergic stimulation. Strong arguments for this role of eNOS come from experiments with eNOS knockout mice, which both in vivo and in isolated heart preparations show a stronger contractile response to catecholamine stimulation [70,72,82]. As eNOS is expressed in the coronary endothelium and within cardiac myocytes the contractile function could be influenced in a paracrine manner by endothelium-derived NO or via autocrine mechanisms by cardiomyocyte derived NO. However, Ca2+ currents are not different in isolated cardiac myocytes from wild type and eNOS knockout mice and thus this finding suggests a more paracrine mode of eNOS action [71,72]. Cardiac myocytes isolated from nNOS knockout hearts showed an increased response to β-adrenergic stimulation in that the extent of contraction was increased. This was most likely the result of elevated Ca2+ currents and increased Ca2+-transients [83,84]. Thus, according to these findings nNOS, like eNOS may contribute to the anti-adrenergic effect of NO in the heart. However, as appears typical for the field of NO research in the heart, there are other reports which suggest just an opposite role for the same isoform. According to Barouch et al. who also used nNOS knockout mice cardiac nNOS might possess a positive inotropic effect in the context of β-adrenergic stimulation [81]. Because this group showed that nNOS formed a complex at the SR membrane with the ryanodine channel a possible mechanism could be that nNOS derived NO induced S-nitrosation of the ryanodine channel. This modification has been shown to enhance the open probability of this channel leading to prolonged Ca2+ transients [85]. Whatever the cardiac effects of eNOS and nNOS are, it remains to be clarified how the spatial separation of NOS isoforms can be converted into a locally restricted action of NO because NO is a highly diffusible molecule which on the basis of diffusion distance should be able to reach all compartments within a cardiac myocyte. A possible barrier, however, which may prevent the spill over from one subcellular compartment to the other would be of course myoglobin acting as an NO scavenger.

Whereas the myoglobin mediated NO dioxygenation had been intensively studied in vitro experimental proof for this function in vivo has only recently been provided. In 1993, Ishibashi et al. reported that the release of cGMP in response to NO donors in aorta, atrium and ventricle was substantially different and these authors speculated that the different myoglobin contents in these tissues represented a major parameter determining the efficacy of NO to induce sGC activity [86]. Experimental proof of the relevance of myoglobin's NO scavenging activity in vivo became possible with the analysis of myoglobin knockout mice. Flögel et al. presented compelling evidence that myoglobin acts as an NO scavenger in vivo [87]. The action of both, exogenous NO supplied as NO solution and the bradykinin-induced increase of endogenous cardiac NO formation were significantly more effective to regulate coronary tone and myocardial contractility in myo–/– mice. This suggests that myoglobin free hearts are under a higher NO "tone" than their WT counterparts. The appearance of met-myoglobin with increasing NO doses directly demonstrated the oxidation of myoglobin's ferrous iron to the ferric form, which is expected as a consequence of the NO dioxygenation. As a caution, it must be noted, that at NO doses sufficient to completely oxidize myoglobin to met-myoglobin, the protective effect of myoglobin vanished. As we will discuss later, such a situation is unlikely to occur in vivo.

Many reports have demonstrated that under pathological conditions there is an upregulation of the inducible NOS isoform within the heart [60,61]. Once formed, this Ca2+-independent NOS isoform is known to release sustained high levels of NO. However, in cardiac myocytes high levels of NO have been demonstrated to exert a negative inotropic effect under basal conditions, to inhibit the respiratory chain function and to induce apoptosis [88,89]. Based on these detrimental effects the concept was developed that the upregulation of iNOS might play a causative role in human and in experimentally induced heart failure. In view of the finding of myoglobin's modulatory role on cardiac NO action it appears important to note that analysis of human myocardial biopsies from heart failure patients as well as from animal models (bovine dilated cardiomyopathy, pacing-induced heart failure in dogs) revealed downregulation of myoglobin expression [90,91]. Thus, the inverse correlation of myoglobin and iNOS expression could favour the development of nitrosative stress within the heart and support the development of heart failure.

However, several transgenic mouse models with cardiomyocyte specific overexpression of either eNOS or iNOS have been generated and functionally analysed [92,93]. It must be noted that despite high level overexpression of iNOS and eNOS with cardiac NOS activities increased up to 300-fold over baseline no obvious pathological cardiac phenotype was observed raising the question of which mechanism allowed adaptation to the chronically elevated NO levels. Subsequent analysis in isolated hearts of iNOS overexpressing mice using functional inactivation of myoglobin by carbon monoxide demonstrated the development of functional depression plus a reduction of the cardiac energy status, shown by reduced phophocreatine and ATP levels [94]. By the use of double transgenic mice which concomitantly were devoid of myoglobin and overexpressed iNOS within the heart, similar results were obtained. Whereas iNOS overexpressing mice showed no signs of heart failure, overexpression of iNOS in a myoglobin-free background led to cardiac hypertrophy, ventricular dilatation and the occurrence of interstitial cardiac fibrosis [95]. As under acute myoglobin inactivation the functional depression of the hearts ex vivo and in vivo went along with an altered cardiac energy status. In line with these findings Mammen et al. found that under hypoxic conditions myoglobin deficient mice developed a systolic dysfunction which could be inhibited by the NOS inhibitor L-NAME [96]. Since chronic hypoxic exposure was associated with upregulation of iNOS in that model the elevated NO formation in myoglobin-free hearts might have accounted for the functional depression.

The work on transgenic mice as cited above not only provides direct proof for the concept that myoglobin modulates the cardiac actions of NO. It also provides insight into the extent to which this reaction occurs in the presence of the high level of NOS activity measured in transgenic mice overexpressing eNOS and iNOS, respectively. The specific activities measured in these mouse models are several fold higher than the highest NOS activities determined in human heart failure specimens [97,98]. However, even with these highest NOS levels myoglobin's capacity to protect the heart from nitrosative stress was still sufficient. Therefore, the concept that iNOS is a causative factor in the development of heart failure needs to be revised. In addition, the finding that either genetical or chemical inactivation of myoglobin led to a reduced energy status implies that myoglobin has the potential to efficiently protect the NO sensitive respiratory chain from nitrosative stress. Brown et al. have shown that NO concentrations as low as 60 nM at low PO2 are sufficient to half-maximally inhibit complex IV of the respiratory chain [99]. Thus, at least in relation to mitochondrial function, myoglobin's NO scavenging potential was sufficient to keep the NO levels below that critical threshold and to inhibit the development of heart failure despite high level NO formation in iNOS-overexpressing mice.

In this context an interesting hypothesis concerning the role of myoglobin in host vs. parasite defence was formulated [100]. The authors raised the question why in Chagas disease the heart muscle appears to be such a preferred site for the chronic survival of trypanosomes although these parasites are highly sensitive to NO released from stimulated, iNOS expressing macrophages. One possible reason which appears plausible on the basis of the summarized findings may be that the efficient myoglobin mediated NO inactivation within the heart may offer a safe place for the trypanosomes to survive. With all the relevant transgenic mice around this hypothesis may now be tested.

The intimate relationship between globins, NO toxicity and mitochondrial protection is not restricted to myoglobin. A short look at the diverse globins found in bacteria, plants and vertebrates, supports the view that NO interaction is an ancestral functions of all globins. In E. coli, flavohemoglobin provides an efficient mechanism to protect these bacteria from NO induced toxicity [101,102]. In Baker's yeast also a flavohemoglobin is found. Early data have shown that its expression is induced under conditions when the respiratory chain is blocked by e.g. antimycin [14,103]. More recent results demonstrate that the yeast hemoglobin is also upregulated in response to NO and plays an important role in the defence against NO action [104]. Given the high sensitivity of the respiratory chain for NO, the yeast system provides evidence that mitochondrial protection is one important evolutionary conserved task of globins.


   6. Summary
Top
 Abstract
 1. Introduction
 2. The globin family...
 3. NO-hemoglobin interactions in...
 4. NO-myoglobin interactions in...
 5. Myoglobin scavenger and...
 6. Summary
References
 
Taken together, hemoglobin and myoglobin represent important modulators of NO function in blood vessels and in the heart, respectively. In the vasculature, hemoglobin's potential to metabolise NO is greatly reduced due to entrapment within erythrocytes. However, further investigation is needed to clearly identify to what extent a hemoglobin-mediated NO release (from SNO–hemoglobin) or hemoglobin-mediated NO formation (by nitrite reduction) may be involved in the local regulation of vascular tone. In cardiac myocytes, myoglobin represents an efficient intrinsic barrier for NO. With this potential, myoglobin is a good candidate to exert this function not only under pathological conditions, it also may control the spatially confined actions of NO released by eNOS localized at the sarcolemmal membrane and nNOS, which associates with the sarcoplasmic reticulum in heart [76,77,81,83,84,105–107]. To what extent myoglobin is expressed in SA and AV nodal cells is unknown and therefore it remains to be investigated whether it modulates the influence of NO on heart rate. If myoglobin is an important determinant of subcellular compartments with respect to NO related processes, the question remains how a compartmentalization of NO action may occur in other myoglobin-free cell types. It will be interesting to see whether the new vertebrate globins, neuroglobin and cytoglobin, which possess a proven NO dioxygenase activity, play a similar role in other cell types [108].


   Acknowledgements
 
The author wishes to dedicate this review to Prof. Jürgen Schrader in thanks for his continuous support. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG) through SFB612, TP A5.


   Notes
 
Time for primary review 17 days


   References
Top
 Abstract
 1. Introduction
 2. The globin family...
 3. NO-hemoglobin interactions in...
 4. NO-myoglobin interactions in...
 5. Myoglobin scavenger and...
 6. Summary
 References
 

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