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Am J Physiol Heart Circ Physiol (July 24, 2003). doi:10.1152/ajpheart.00147.2003
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Submitted on February 19, 2003
Accepted on July 8, 2003

Hypoxia-Induced Left Ventricular Dysfunction in Myoglobin Deficient Mice

Pradeep P.A. Mammen1*, Shane B. Kanatous1, Ivan S. Yuhanna2, Philip W. Shaul2, Mary G. Garry1, Robert S. Balaban3, and Daniel J. Garry4

1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
2 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
3 Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
4 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

* To whom correspondence should be addressed. E-mail: pradeep.mammen{at}utsouthwestern.edu.

Myoglobin deficient mice are viable and have preserved cardiac function due to their ability to mount a complex compensatory response involving increased vascularization and the induction of the hypoxia gene program (HIF-1{alpha}, ePAS, hsp27, etc.). In order to further define and explore functional roles for myoglobin, we challenged age and gender-matched wild type and myoglobin null mice to chronic hypoxia (10% oxygen for 1 day to 3 weeks). We observed a 30% reduction in cardiac systolic function in the myoglobin mutant mice exposed to chronic hypoxia with no changes observed in the wild type control hearts. The cardiac dysfunction observed in the hypoxic myoglobin null mice was reversible with reexposure to normoxic conditions and could be prevented with treatment of an inhibitor of nitric oxide synthases. These results support the conclusion that hypoxia-induced cardiac dysfunction in myoglobin null mice occurs via a NO mediated mechanism. Utilizing enzymatic assays for nitric oxide synthases and immunohistochemical analyses we observed a marked induction of iNOS in the hypoxic myoglobin mutant ventricle compared to the wild type hypoxic control ventricles. These new data establish that myoglobin is an important cytoplasmic cardiac hemoprotein that functions in regulating NO homeostasis within cardiomyocytes.




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