Adaptation of the myoglobin knockout mouse to hypoxic stress.
Myoglobin knockout (myo-/-) mice were previously reported to show no obvious phenotype but revealed several compensatory mechanisms that include increases in cardiac capillary density, coronary flow, and hemoglobin. The aim of this study was to investigate whether severe hypoxic stress can exhaust these compensatory mechanisms and whether this can be monitored on the gene and protein level. Myo-/- and wild-type (WT) mice we e exposed to hypoxia (10% O(2)) fo 2 wk. Thereafter hemodynamic parameters were investigated by invasive measurement combined with magnetic resonance imaging. Cardiac gene and protein expression were analyzed using cDNA arrays and two-dimensional gel electrophoresis plus mass spectrometry, respectively. Hematocrit levels increased from 44% (WT) and 48% (myo-/-) to 72% in both groups. Similar to WT controls, hypoxic myo-/- animals maintained stable cardiovascular function (mean arterial blood pressure 82.4 mmHg, ejection fraction 72.5%). Cardiac gene expression of hypoxic myo-/- mice differed significantly from WT controls in 17 genes (e.g., keratinocyte lipid binding protein +202%, cytochrome c oxidase Vb +41%). Interestingly, hypoxia inducible factor-1alpha remained unchanged in both groups. Proteome analysis revealed reduced levels of heart fatty acid-binding protein and heat shock protein 27 both in hypoxic myo-/- and WT mice. Our data thus demonstrate that myo-/- mice do not decompensate du ing hypoxic st ess but a e surprisingly well adapted. Changes in ene gy metabolism of fatty acids may contribute to the robustness of myoglobin-deficient mice.
Schlieper
Georg
G
Department of Cardiovascular Physiology, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
Kim
Jie-Hoon
JH
Molojavyi
Andrei
A
Jacoby
Christoph
C
Laussmann
Tim
T
Flögel
Ulrich
U
Gödecke
Axel
A
Schrader
Jürgen
J
D000222:Adaptation, Physiological / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001772:Blood Cell Count; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology; D000860:Hypoxia / Q000503:physiopathology*; D017403:In Situ Hybridization; D008279:Magnetic Resonance Imaging; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009211:Myoglobin / Q000235:genetics* / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000235:genetics / Q000502:physiology
D018076:DNA, Complementary; D009211:Myoglobin; D012333:RNA, Messenger