Published online before print May 10, 2007, doi: 10.1161/CIRCRESAHA.107.152488
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2007 American Heart Association, Inc.
Integrative Physiology |
Nitrite Reductase Function of Deoxymyoglobin
Oxygen Sensor and Regulator of Cardiac Energetics and Function
From the University Hospital Aachen, Department of Medicine, Division of Cardiology, Pulmonary and Vascular Diseases (T.R., C.D., U.H.-C., M.K.), Aachen; and the Department of Cardiovascular Physiology (U.F., J.S.), Heinrich-Heine-University Düsseldorf, Germany.
Correspondence Tienush Rassaf, MD, University Hospital Aachen, Department of Medicine, Division of Cardiology, Pulmonary and Vascular Diseases, Pauwelsstr. 30, D-52074 Aachen, Germany. E-mail trassaf{at}ukaachen.de
Although the primary function of myoglobin (Mb) has been considered to be cellular oxygen storage and supply, recent studies have suggested to classify Mb as a multifunctional allosteric enzyme. In the heart, Mb acts as a potent scavenger of nitric oxide (NO) and contributes to the attenuation of oxidative damage. Here we report that a dynamic cycle exists in which a decrease in tissue oxygen tension drives the conversion of Mb from being an NO scavenger in normoxia to an NO producer in hypoxia. The NO generated by reaction of deoxygenated Mb with nitrite is functionally relevant and leads to a downregulation of cardiac energy status, which was not observed in mice lacking Mb. As a consequence, myocardial oxygen consumption is reduced and cardiac contractility is dampened in wild-type mice. We propose that this pathway represents a novel homeostatic mechanism by which a mismatch between oxygen supply and demand in muscle is translated into the fractional increase of deoxygenated Mb exhibiting enhanced nitrite reductase activity. Thus, Mb may act as an oxygen sensor which through NO can adjust muscle energetics to limited oxygen supply.
Key Words: nitrite • hypoxia • myoglobin • cardiac function
This article has been cited by other articles:
 |
|
 |
|
  F. M. Gonzalez, S. Shiva, P. S. Vincent, L. A. Ringwood, L.-Y. Hsu, Y. Y. Hon, A. H. Aletras, R. O. Cannon III, M. T. Gladwin, and A. E. Arai Nitrite Anion Provides Potent Cytoprotective and Antiapoptotic Effects as Adjunctive Therapy to Reperfusion for Acute Myocardial Infarction Circulation, June 10, 2008; 117(23): 2986 - 2994. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Vinogradov and L. Moens Diversity of Globin Function: Enzymatic, Transport, Storage, and Sensing J. Biol. Chem., April 4, 2008; 283(14): 8773 - 8777. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Rosenberger, M. Goldfarb, A. Shina, S. Bachmann, U. Frei, K.-U. Eckardt, T. Schrader, S. Rosen, and S. N. Heyman Evidence for sustained renal hypoxia and transient hypoxia adaptation in experimental rhabdomyolysis-induced acute kidney injury Nephrol. Dial. Transplant., April 1, 2008; 23(4): 1135 - 1143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Grubina, S. Basu, M. Tiso, D. B. Kim-Shapiro, and M. T. Gladwin Nitrite Reductase Activity of Hemoglobin S (Sickle) Provides Insight into Contributions of Heme Redox Potential Versus Ligand Affinity J. Biol. Chem., February 8, 2008; 283(6): 3628 - 3638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Gladwin Evidence Mounts That Nitrite Contributes to Hypoxic Vasodilation in the Human Circulation Circulation, February 5, 2008; 117(5): 594 - 597. [Full Text] [PDF]
|
|
|
|
 |
|
 T. S. Isbell, M. T. Gladwin, and R. P. Patel Hemoglobin oxygen fractional saturation regulates nitrite-dependent vasodilation of aortic ring bioassays Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2565 - H2572. [Abstract] [Full Text] [PDF]
|
|