title: Pre- and post-conditional inhibition of prolyl-4-hydroxylase domain enzymes protects the heart from an ischemic insult.
abstract: Several genetically modified mouse models implicated that prolyl-4-hydroxylase domain (PHD) enzymes are critical mediators for protecting tissues from an ischemic insult including myocardial infarction by affecting the stability and activation of hypoxia-inducible factor (HIF)-1 and HIF-2. Thus, the current efforts to develop small-molecule PHD inhibitors open a new therapeutic option for myocardial tissue protection during ischemia. Therefore, we aimed to investigate the applicability and efficacy of pharmacological HIFα stabilization by a small-molecule PHD inhibitor in the heart. We tested for protective effects in the acute phase of myocardial infarction after pre- or post-conditional application of the inhibitor. Application of the specific PHD inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) resulted in HIF-1α and HIF-2α accumulation in heart muscle cells in vitro and in vivo. The rapid and robust responsiveness of cardiac tissue towards ICA was further confirmed by induction of the known HIF target genes heme oxygenase-1 and PHD3. Pre- and post-conditional treatment of mice undergoing myocardial infarction resulted in a significantly smaller infarct size. Tissue protection from ischemia after pre- or post-conditional ICA treatment demonstrates that there is a therapeutic time window for the application of the PHD inhibitor (PHI) post-myocardial infarction, which might be exploited for acute medical interventions.
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Vogler
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.|DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Zieseniss
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, Humboldtallee 23, 37073, Göttingen, Germany.|DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany.
authors.forename: Amke R
authors.initials: AR
authors.lastname: Hesse
authors.affiliation: Institute of Pharmacology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.|DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany.
authors.forename: Elif
authors.initials: E
authors.lastname: Levent
authors.affiliation: Institute of Pharmacology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.|DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Tiburcy
authors.affiliation: Inorganic Chemistry and Organometallic Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander-University, Erlangen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Heinze
authors.affiliation: Inorganic Chemistry and Organometallic Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander-University, Erlangen, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Burzlaff
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schley
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen, Germany.
authors.forename: Kai Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Willam
authors.affiliation: Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, Humboldtallee 23, 37073, Göttingen, Germany. doerthe.katschinski@med.uni.goettingen.de.|DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany. doerthe.katschinski@med.uni.goettingen.de.
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D057775:Ischemic Postconditioning; D019157:Ischemic Preconditioning, Myocardial; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism; D064800:Prolyl-Hydroxylase Inhibitors / Q000627:therapeutic use*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C000608512:2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido)acetic acid; D002316:Cardiotonic Agents; C485502:HIF-2 protein, mouse; D051793:Hypoxia-Inducible Factor 1; D007546:Isoquinolines; D064800:Prolyl-Hydroxylase Inhibitors; D014157:Transcription Factors; D005998:Glycine
keywords: HIF; Hypoxia; Ischemia; Prolyl-hydroxylase inhibitor