title: Stabilization of hypoxia inducible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarction in rats.
abstract: Prolyl hydroxylase domain-containing enzymes (PHD) hydroxylate a proline residue that controls the degradation of hypoxia inducible factor (HIF). Hypoxia inhibits this hydroxylation thus increasing HIF levels. HIF is upregulated in ischemic tissues, growing tumors and in nonischemic, mechanically stressed myocardium. Pharmacological inhibition of prolyl 4-hydroxylase (P4-H) stabilizes HIF-protein in vitro and may modulate collagen turnover. The aims of this study were to investigate whether inhibition of P4-H protects myocardium against ischemia, and whether the observed effects are related to modulation of collagen metabolism or due to the stabilization of HIF.
  
  
  METHODS
  Rats were treated with a specific P4-H inhibitor (P4-HI) or vehicle starting 2 days before induction of myocardial infarction (MI). Rats were investigated 7 or 30 days after MI. Induction of HIF-1alpha and -2alpha was visualized by immunohistochemistry. Expression of growth factors (connective tissue growth factor, Osteopontin) and mRNA expression and protein levels of Collagen I and III as well as HIF-2alpha were measured.
  
  
  RESULTS
  P4-HI augments HIF in the myocardium as early as 24 h after treatment. P4-HI did not alter the MI-induced enhanced expression of growth factors and collagen. Treatment with P4-HI significantly reduced heart and lung weight, improved left ventricular contractility, prevented left ventricular enlargement and improved left ventricular ejection fraction without affecting infarct size after 30 days.
  
  
  CONCLUSIONS
  Specific inhibition of the P4-H improved cardiac function without affecting the infarct size after experimental myocardial infarction in rats. Stabilization of HIF rather than inhibition of collagen maturation by P4-HI may prevent cardiac remodeling after MI.
authors.affiliation: Department of Cardiology, West-German Heart Center Essen, University of Duisburg-Essen, Essen, Germany. sebastian.philipp@medizin.uni-essen.de
authors.forename: Sebastian
authors.initials: S
authors.lastname: Philipp
authors.forename: Jan Steffen
authors.initials: JS
authors.lastname: Jürgensen
authors.forename: Jens
authors.initials: J
authors.lastname: Fielitz
authors.forename: Wanja M
authors.initials: WM
authors.lastname: Bernhardt
authors.forename: Alexander
authors.initials: A
authors.lastname: Weidemann
authors.forename: Astrid
authors.initials: A
authors.lastname: Schiche
authors.forename: Bernhard
authors.initials: B
authors.lastname: Pilz
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.forename: Roland
authors.initials: R
authors.lastname: Willenbrock
mesh_terms: D000818:Animals; D001483:Base Sequence; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D017931:DNA Primers; D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D003094:Collagen; D011393:Procollagen-Proline Dioxygenase