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Differential Effects of Pharmacological HIF Preconditioning of Donors Versus Recipients in Rat Cardiac Allografts
Author(s) -
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.
Publication year - 2013
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.12064
Subject(s) - medicine , ischemia , reperfusion injury , ischemic preconditioning , hypoxia (environmental) , heart transplantation , myocyte , pharmacology , transplantation , innate immune system , immunology , immune system , chemistry , organic chemistry , oxygen
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.