Conditional HIF-1alpha expression produces a reversible cardiomyopathy.
BACKGROUND
The response to hypoxia in tissues is regulated by the heterodimeric transcription factor Hypoxia Inducible Factor-1 (HIF-1).


RESULTS
We have created a strain of mice with inducible cardiomyocyte-specific expression of a mutated, oxygen-stable, form of HIF-1alpha. Cardiac function steadily decreased with transgene expression, but recovered after the transgene was turned off. Using long-oligo microarrays, we identified 162 transcripts more than 3-fold dysregulated in these hearts after transgene expression. Among the down-regulated genes the transcript for SERCA was reduced 46% and the protein 92%. This led us to an evaluation of calcium flux that showed diminished reuptake of cytoplasmic calcium in myocytes from these hearts, suggesting a mechanism for cardiac dysfunction.


CONCLUSIONS
These results provide a deeper understanding of transcriptional activity of HIF in the heart, and show that enhanced HIF-1 activity is sufficient to cause contractile dysfunction in the adult heart. HIF is stabilized in the myocardium of patients with ischemic cardiomyopathy, and our results suggest that HIF could be contributing directly to the contractile dysfunction in this disease.
Bekeredjian
Raffi
R
Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
Walton
Chad B
CB
MacCannell
Keith A
KA
Ecker
Jennifer
J
Kruse
Fred
F
Outten
Joel T
JT
Sutcliffe
David
D
Gerard
Robert D
RD
Bruick
Richard K
RK
Shohet
Ralph V
RV
D000818:Animals; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004452:Echocardiography; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases