title: Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury.
abstract: Prolylhydroxylase domain proteins (PHD) are cellular oxygen-sensing molecules that regulate the stability of the α-subunit of the transcription factor hypoxia inducible factor (HIF)-1. HIF-1 affects cardiac development as well as adaptation of the heart toward increased pressure overload or myocardial infarction. We have disrupted PHD2 in cardiomyocytes (cPhd (-/-)) using Phd2(flox/flox) mice in combination with MLCvCre mice, which resulted in HIF-1α stabilization and activation of HIF target genes in the heart. Although cPhd2(-/-) mice showed no gross abnormalities in cardiac filament structure or function, we observed a significant increased cardiac capillary area in those mice. cPhd2 (-/-) mice did not respond differently to increased mechanical load by transverse aortic constriction compared with their wild-type (wt) littermates. After ligation of the left anterior descending artery, however, the area at risk and area of necrosis were significantly smaller in the cPhd2(-/-) mice compared with Phd2 wt mice in line with the described pivotal role of HIF-1α for tissue protection in case of myocardial infarction. This correlated with a decreased number of apoptotic cells in the infarcted myocardium in the cPhd2(-/-) mice and significantly improved cardiac function 3 weeks after myocardial infarction.
authors.affiliation: Department of Cardiovascular Physiology, Universitätsmedizin Göttingen, Georg-August University Göttingen, Göttingen, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Hölscher
authors.forename: Monique
authors.initials: M
authors.lastname: Silter
authors.forename: Sabine
authors.initials: S
authors.lastname: Krull
authors.forename: Melanie
authors.initials: M
authors.lastname: von Ahlen
authors.forename: Amke
authors.initials: A
authors.lastname: Hesse
authors.forename: Peter
authors.initials: P
authors.lastname: Schwartz
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
authors.forename: Anke
authors.initials: A
authors.lastname: Zieseniss
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D055785:Gene Knockdown Techniques; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009336:Necrosis / Q000201:enzymology / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase; D055550:Protein Stability
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases