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

Abstract

Ischemia-reperfusion injury (IRI) induces hypoxiainducible 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-a stabilizing prolyl hydroxylase inhibitor (FG-4497) on IRI or allograft survival. Ex vivo ischemia of the heart increased HIF-1a expression in a time-and temperature-dependent fashion. Immunohistochemistry localized HIF-1a to all cardiac cell types. After reperfusion, HIF-1a 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 longterm 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-a 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 Role of Hypoxia-Inducible Factors in Organ Donation and Transplantation: The Current Perspective and Future Opportunities

“…In a recent publication in the American Journal of Transplantation Kerä nen et al demonstrated the protection that could be conferred by treating recipients over donors using a rodent model of cardiac IRI and transplantation (38). Pretreating donor rodents 4 h prior to IRI with FG-4497 caused an increase in troponin T release and increased cardiomyocyte apoptosis compared to controls, a finding that is at odds with Bernhardt et al who demonstrated renal protection when the same agent was administered to rat kidney donors 6 h prior to procurement (25).…”

Donor Treatment With a Hypoxia‐Inducible Factor‐1 Agonist Prevents Donation After Cardiac Death Liver Graft Injury in a Rat Isolated Perfusion Model

“…Preconditional activation of HIF-1 by a HIF-agonist (EDHB) significantly decreases liver ischemia/reperfusion (I/R) injury through decreased mitochondrial depolarization and prevention of mitochondrial injury (8). The pharmaceutical activation of HIF-1 with the use of synthetic HIF agonists also results in early recovery of graft function in renal, heart and aortic allograft transplantation (9)(10)(11)(12)(13).…”

Hypoxia-inducible factor controls immunoregulatory properties of myeloid cells in mouse cardiac allografts - an experimental study

“…The important role of HIF‐1α in myeloid cell‐mediated inflammation has been previously established both in vivo and in vitro . We previously found that pharmacologic stabilization of HIF in the heart donor exacerbated IRI . Interestingly, in this study, we found that loss of HIF‐1α in myeloid cells did not affect the influx of CD11b + macrophages and CD11c + dendritic cells into fully MHC‐mismatched cardiac allografts at 6 h and 5 days after transplantation.…”