Myoglobin: A scavenger of bioactive NO

Abstract

The present study explored the role of myoglobin (Mb) in cardiac NO homeostasis and its functional relevance by employing isolated hearts of wild-type (WT) and myoglobin knockout mice. 1 H NMR spectroscopy was used to measure directly the conversion of oxygenated Mb (MbO2) to metmyoglobin (metMb) by reaction with NO. NO was applied intracoronarily (5 nM to 25 M), or its endogenous production was stimulated with bradykinin (Bk; 10 nM to 2 M). We found that infusion of authentic NO solutions dose-dependently (> 2.5 M NO) increased metMb formation in WT hearts that was rapidly reversible on cessation of NO infusion. Likewise, Bk-induced release of NO was associated with significant metMb formation in the WT (>1 M Bk and IIa skeletal and cardiac muscle tissue (1). As a major breakthrough in understanding globular protein structure, its tertiary structure was derived from x-ray diffraction studies by John Kendrew and his colleagues as early as the 1950s (2). Mb is a relatively small (M r 16,700) and densely packed protein consisting of a single polypeptide chain of 153 amino acid residues. It contains an iron-porphyrin heme group identical to that of hemoglobin (Hb), and like Hb is capable of reversible oxygenation and deoxygenation. In mammals, half O 2 saturation of Mb is achieved at an intracellular O 2 partial pressure as low as 2.4 mmHg (1 mmHg ϭ 133 Pa; ref.3), suggesting a predominance of oxygenated Mb (MbO 2 ) under basal conditions. Mb's function as an oxygen store is well accepted. Mb serves as a short-term O 2 reservoir in exercising skeletal muscle and in the beating heart, tiding the muscle over from one contraction to the next (4). In diving mammals, the concentrations of Mb exceed those of terrestrial mammals up to 10-fold, and Mb most likely serves for the extension of diving time when pulmonary ventilation ceases (5). Similarly, in mammals and humans adapted to high altitudes, Mb is expressed in high concentrations in skeletal muscle (6).It has been proposed that Mb facilitates intracellular delivery of O 2 , in that Mb adjacent to the cell membrane picks up oxygen, traverses the cytosol by translational diffusion to unload O 2 in the vicinity of mitochondria, and finally diffuses back to the cell membrane in the deoxygenated state (7). This circuit, termed ''facilitated O 2 diffusion,'' may be a critical link between capillary O 2 supply and O 2 -consuming cytochromes within mitochondria in the steady state. Facilitated O 2 diffusion has been unambiguously demonstrated in concentrated Mb solutions (8), but experiments carried out in isolated cells, papillary muscle, and at the whole organ level have yielded conflicting results (9-11). Likewise, model calculations have both refuted and supported the contribution of Mb-bound O 2 to total O 2 flux (11, 12).The recent generation of transgenic mice lacking Mb has shed new light on the role of Mb in the intracellular delivery of O 2 (13,14). Loss of Mb led to a surprisingly benign phenotype, with exercise and reproductive capacity, as well as cardiac and ...

Endogenous myoglobin in human breast cancer is a hallmark of luminal cancer phenotype

“…Myoglobin has different known or alleged functions in muscle tissue including short-term O 2 storage and buffering, facilitating O 2 diffusion, scavenging of NO and ROS and also the reverse (peroxidase activity, NO production) and might be involved in FA metabolism (Wittenberg, 1970;Wittenberg et al, 1975;Khan et al, 1998;Flögel et al, 2001Flögel et al, , 2004Ordway and Garry, 2004;HendgenCotta et al, 2008;Masuda et al, 2008). The functions of Mb in nonmuscle tissues are elusive so far.…”

“…Another, more controversially discussed role is Mbs' facilitation of O 2 diffusion within muscle cells (Wittenberg, 1970;Jürgens et al, 1994). Although Mb knockout mice exhibited normal exercise capacity and no signs of compromised cardiac energetics due to multiple systemic compensations (Garry et al, 1998;Gödecke et al, 1999), follow-up studies stressed the importance of functional Mb in maintaining nitric oxide (NO) homeostasis in muscle through either scavenging (Flögel et al, 2001) or producing the NO molecule (Hendgen-Cotta et al, 2008). That way, Mb might participate in tuning vasodilatory responsiveness and protecting the respiratory chain from NO inhibition (Brunori, 2001).…”

Catalytic peroxidation of nitrogen monoxide and peroxynitrite by globins

“…In particular, NADH-metHb andmetMb reductases catalyze the conversion of heme-Fe(III) to heme-Fe(II) in vivo. As a matter of fact, the enzymatic hemeFe(III) reduction is the rate-limiting step of the whole process, this representing a severe limitation for the efficiency of these mechanisms in vivo (4,28,(35)(36)(37)(38)(39)(40)(41)(42)(43).…”

Neuroglobin protects against nitric oxide toxicity

“…This primordial oxygenase activity is still apparent in the capacity of hemoglobin [6] and myoglobin [4] to scavenge NO, and appears to have pathophysiological significance, since overexpression of inducible NO synthase (NOS) causes heart failure in myoglobin-knockout mice [7]. Because Ngb binds NO [23], its neuroprotective action may also relate to NO scavenging [1,8].…”