Hypoxia-induced left ventricular dysfunction in myoglobin-deficient mice.
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 (hypoxia-inducible factor-1alpha, endothelial PAS, heat shock protein27, etc.). 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 wk). 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 (NO) 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 NO synthases and immunohistochemical analyses, we observed a marked induction of inducible NO synthase in the hypoxic myoglobin mutant ventricle compared with the wild-type hypoxic control ventricle. These new data establish that myoglobin is an important cytoplasmic cardiac hemoprotein that functions in regulating NO homeostasis within cardiomyocytes.
Mammen
Pradeep P A
PP
Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8573, USA.
Kanatous
Shane B
SB
Yuhanna
Ivan S
IS
Shaul
Philip W
PW
Garry
Mary G
MG
Balaban
Robert S
RS
Garry
Daniel J
DJ
D000818:Animals; D002908:Chronic Disease; D006706:Homeostasis / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009211:Myoglobin / Q000235:genetics* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D013599:Systole / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
D009211:Myoglobin; D009569:Nitric Oxide