PMID- 22258630
OWN - NLM
STAT- MEDLINE
DCOM- 20120716
LR  - 20190412
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Linking)
VI  - 94
IP  - 1
DP  - 2012 Apr 1
TI  - Unfavourable consequences of chronic cardiac HIF-1alpha stabilization.
PG  - 77-86
LID - 10.1093/cvr/cvs014 [doi]
AB  - AIMS: The hypoxia-inducible factor-1 (HIF-1) is the master modulator of hypoxic 
      gene expression. The effects of chronically stabilized cardiac HIF-1alpha and its 
      role in the diseased heart are not precisely known. The aims of this study were 
      as follows: (i) to elucidate consequences of HIF-1alpha stabilization in the heart; 
      (ii) to analyse long-term effects of HIF-1alpha stabilization with ageing and the 
      ability of the HIF-1alpha overexpressing hearts to respond to increased mechanical 
      load; and (iii) to analyse HIF-1alpha protein levels in failing heart samples. 
      METHODS AND RESULTS: In a cardiac-specific HIF-1alpha transgenic mouse model, 
      constitutive expression of HIF-1alpha leads to changes in capillary area and shifts 
      the cardiac metabolism towards glycolysis with a net increase in glucose uptake. 
      Furthermore, Ca(2+) handling is altered, with increased Ca(2)(+) transients and 
      faster intracellular [Ca(2+)] decline. These changes are associated with 
      decreased expression of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a but 
      elevated phosphorylation of phospholamban. HIF-1alpha transgenic mice subjected to 
      transverse aortic constriction exhibited profound cardiac decompensation. 
      Moreover, cardiomyopathy was also seen in ageing transgenic mice. In parallel, we 
      found an increased stabilization of HIF-1alpha in heart samples of patients with 
      end-stage heart failure. CONCLUSION: Changes induced with transgenic cardiac 
      HIF-1alpha possibly mediate beneficial effects in the short term; however, with 
      increased mechanical load and ageing they become detrimental for cardiac 
      function. Together with the finding of increased HIF-1alpha protein levels in samples 
      from human patients with cardiomyopathy, these data indicate that chronic HIF-1alpha 
      stabilization drives autonomous pathways that add to disease progression.
FAU - Holscher, Marion
AU  - Holscher M
AD  - Department of Cardiovascular Physiology, Universitatsmedizin, 
      Georg-August-University Gottingen, Humboldtallee 23, 37073 Gottingen, Germany.
FAU - Schafer, Katrin
AU  - Schafer K
FAU - Krull, Sabine
AU  - Krull S
FAU - Farhat, Katja
AU  - Farhat K
FAU - Hesse, Amke
AU  - Hesse A
FAU - Silter, Monique
AU  - Silter M
FAU - Lin, Yun
AU  - Lin Y
FAU - Pichler, Bernd J
AU  - Pichler BJ
FAU - Thistlethwaite, Patricia
AU  - Thistlethwaite P
FAU - El-Armouche, Ali
AU  - El-Armouche A
FAU - Maier, Lars S
AU  - Maier LS
FAU - Katschinski, Dorthe M
AU  - Katschinski DM
FAU - Zieseniss, Anke
AU  - Zieseniss A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120118
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (phospholamban)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - EC 7.2.2.10 (Atp2a2 protein, mouse)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Age Factors
MH  - Animals
MH  - Calcium Signaling/genetics
MH  - Calcium-Binding Proteins/metabolism
MH  - Capillaries/metabolism
MH  - Cardiomyopathies/genetics/*metabolism/physiopathology
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Gene Expression Regulation
MH  - Glucose/metabolism
MH  - Glycolysis/genetics
MH  - Heart Failure/genetics/*metabolism/physiopathology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - Myocytes, Cardiac/*metabolism
MH  - Phosphorylation
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism
MH  - Time Factors
MH  - Up-Regulation
MH  - Ventricular Function, Left
EDAT- 2012/01/20 06:00
MHDA- 2012/07/17 06:00
CRDT- 2012/01/20 06:00
PHST- 2012/01/20 06:00 [entrez]
PHST- 2012/01/20 06:00 [pubmed]
PHST- 2012/07/17 06:00 [medline]
AID - cvs014 [pii]
AID - 10.1093/cvr/cvs014 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2012 Apr 1;94(1):77-86. doi: 10.1093/cvr/cvs014. Epub 2012 Jan 
      18.