Differential Effects of Pharmacological HIF Preconditioning of Donors Versus Recipients in Rat Cardiac Allografts

• Published in: American journal of transplantation Vol. 13; no. 3; pp. 600 - 610
• Main Authors: Keränen, M. A. I., Tuuminen, R., Syrjälä, S., Krebs, R., Walkinshaw, G., Flippin, L. A., Arend, M., Koskinen, P. K., Nykänen, A. I., Lemström, K. B.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 01.03.2013; Wiley Subscription Services, Inc
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Biomarkers - analysis; Enzyme Inhibitors - pharmacology; Heart - physiopathology; Heart Transplantation; Hypoxia; Hypoxia-Inducible Factor 1 - metabolism; Inflammation - diagnosis; Inflammation - metabolism; ischemia; ischemia/reperfusion injury; Ischemic Preconditioning; Macrophages - metabolism; Macrophages - pathology; Male; Medical sciences; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - pathology; Procollagen-Proline Dioxygenase - antagonists & inhibitors; Rats; Rats, Inbred WF; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; transplantation; Transplantation, Homologous; Heart; Suboptimal donor; Temperature; Rat; ischemia/reperfusion injury; ischemic preconditioning; Environmental factor; Cardiovascular disease; Transplantation; Homotransplantation; Reperfusion; Ischemia; Surgery; Graft; Human; Oxygen; Cold; Rodentia; Recipient; Vertebrata; Mammalia; Treatment; Animal; Hypoxia; Circulatory system; Preconditioning; Comparative study
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.12064

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. The authors report that pretreatment of cardiac allograft donors or recipients with the novel prolyl‐hydroxylase inhibitor FG‐4497 leads to divergent outcomes in a rat cardiac allograft transplantation model.