title: Differential effects of pharmacological HIF preconditioning of donors versus recipients in rat cardiac allografts.
abstract: Ischemia-reperfusion injury (IRI) induces hypoxia-inducible factor-1 (HIF-1) in the myocardium, but the consequences remain elusive. We investigated HIF-1 activation during cold and warm ischemia and IRI in rat hearts and cardiac syngrafts. We also tested the effect of HIF-α stabilizing prolyl hydroxylase inhibitor (FG-4497) on IRI or allograft survival. Ex vivo ischemia of the heart increased HIF-1α expression in a time- and temperature-dependent fashion. Immunohistochemistry localized HIF-1α to all cardiac cell types. After reperfusion, HIF-1α immunoreactivity persisted in smooth muscle cells and cardiomyocytes in the areas with IRI. This was accompanied with a transient induction of protective HIF-1 downstream genes. Donor FG-4497 pretreatment for 4 h enhanced IRI in cardiac allografts as evidenced by an increase in cardiac troponin T release, cardiomyocyte apoptosis, and activation of innate immunity. Recipient FG-4497 pretreatment for 4 h decreased infiltration of ED1(+) macrophages, and mildly improved the long-term allograft survival. In syngrafts donor FG-4497 pretreatment increased activation of innate immunity, but did not induce myocardial damage. We conclude that the HIF-1 pathway is activated in heart transplants. We suggest that pharmacological HIF-α preconditioning of cardiac allografts donors would not lead to clinical benefit, while in recipients it may result in antiinflammatory effects and prolonged allograft survival.
authors: Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors: M A I
authors: MA
authors: Keränen
authors: R
authors: R
authors: Tuuminen
authors: S
authors: S
authors: Syrjälä
authors: R
authors: R
authors: Krebs
authors: G
authors: G
authors: Walkinshaw
authors: L A
authors: LA
authors: Flippin
authors: M
authors: M
authors: Arend
authors: P K
authors: PK
authors: Koskinen
authors: A I
authors: AI
authors: Nykänen
authors: K B
authors: KB
authors: Lemström
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000503:physiopathology*; D016027:Heart Transplantation; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007249:Inflammation / Q000175:diagnosis / Q000378:metabolism; D019194:Ischemic Preconditioning; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D051381:Rats; D011920:Rats, Inbred WF; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D051793:Hypoxia-Inducible Factor 1; D011393:Procollagen-Proline Dioxygenase