title: Cardiomyocyte-Specific Transgenic Expression of Prolyl-4-Hydroxylase Domain 3 Impairs the Myocardial Response to Ischemia.
abstract: OBJECTIVE
  The prolyl-4-hydroxylase domain (PHD) enzymes are representing novel therapeutic targets for ischemic tissue protection. Whereas the consequences of a knock out of the PHDs have been analyzed in the context of cardioprotection, the implications of PHD overexpression is unknown so far.
  
  
  RESULTS
  We generated cardiomyocyte-specific PHD3transgenic mice (cPhd3tg). Resting cPhd3tg mice did not show constitutive accumulation of HIF-1α or HIF-2α or changes in HIF target gene expression in the heart. Cardiac function was followed up for 14 months in these mice and found to be unchanged. After challenging the cPhd3tg mice with ligation of the left anterior descending artery, HIF-1α/-2α accumulation in the left ventricles was blunted. This was associated with a significantly increased infarct size of the cPhd3tg compared to wild type mice.
  
  
  CONCLUSIONS
  Whereas overexpression of PHD3 in the resting state does not significantly influence cardiac function, it is crucial for the cardiac response to ischemia by affecting HIFα accumulation in the ischemic tissue.
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Zieseniss
authors.forename: Amke R
authors.initials: AR
authors.lastname: Hesse
authors.forename: Aline
authors.initials: A
authors.lastname: Jatho
authors.forename: Sabine
authors.initials: S
authors.lastname: Krull
authors.forename: Marion
authors.initials: M
authors.lastname: Hölscher
authors.forename: Sabine
authors.initials: S
authors.lastname: Vogel
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C522722:PHD3 protein, mouse