Facilitated O2 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 (9C11)
Facilitated O2 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 (9C11). NO concentration fits well with the hypothesis that in the presence of Mb, a continuous Smilagenin degradation of NO takes place by reaction of MbO2 + NO to metMb + NO3?, Smilagenin thereby effectively reducing cytosolic NO concentration. This breakdown protects myocytic cytochromes against transient rises in cytosolic NO. Regeneration of metMb by metMb reductase to Mb and subsequent association with O2 leads to reformation of MbO2 available for another NO degradation cycle. Our data indicate that this cycle is crucial in the breakdown of NO and substantially determines the doseCresponse curve of the NO effects on coronary blood flow and cardiac contractility. Myoglobin (Mb) is an important intracellular O2-binding hemoprotein found in the cytoplasm of vertebrate type I 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 (Mr 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 O2 saturation of Mb is achieved at an intracellular O2 partial pressure as low as 2.4 mmHg (1 mmHg = 133 Pa; ref. 3), suggesting a predominance of oxygenated Mb (MbO2) under basal conditions. Mb’s function as an oxygen store is well accepted. Mb serves as a short-term O2 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 O2, in that Mb adjacent to the cell membrane picks up oxygen, traverses the cytosol by translational diffusion to unload O2 in the vicinity of mitochondria, and finally diffuses back to the cell membrane in the deoxygenated state (7). This circuit, termed facilitated O2 diffusion, may be a critical link between capillary O2 supply and O2-consuming cytochromes within mitochondria in the steady state. Facilitated O2 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 Rabbit Polyclonal to MEKKK 4 yielded conflicting results (9C11). Likewise, model calculations have both refuted and supported the contribution of Mb-bound O2 to total O2 flux (11, 12). The recent generation of transgenic mice lacking Mb has shed new light on the role of Mb in Smilagenin the intracellular delivery of O2 (13, 14). Loss of Mb led to a surprisingly benign phenotype, with exercise and reproductive capacity, as well as cardiac and skeletal function, largely unaltered (13). Maintenance of function was accomplished by the activation of numerous compensatory mechanisms (14). However, direct evidence for an important role of Mb in facilitating O2 diffusion was only Smilagenin recently produced by experiments employing CO to acutely inactivate Mb in the isolated wild-type (WT) heart by using hearts of Mb knockout (myo?/?) mice as appropriate controls (15). Additionally, supportive evidence is derived from observations on single isolated cardiomyocytes (15, 16). Mb is a molecular relative.