Effect of graft preservation and acute rejection on hypoxia-inducible factor-1 in rat cardiac allografts.
Hypoxia plays an integral part in cardiac transplantation as prolonged graft preservation is an individual risk factor for the development of cardiac allograft vasculopathy (CAV). In this study we characterized the role of hypoxia-inducible factor-1 (HIF-1) during prolonged graft preservation, ischemia-reperfusion (I/R), acute rejection, and chronic rejection. Heart transplantations were performed from Dark Agouti (DA) to Wister-Furth (allo) or DA to DA (syn) rats, without immunosuppression (acute rejection model, harvested at day 5) or with cyclosporine (chronic rejection model, harvested at day 60). To study the effect of preservation on HIF-1 regulation, normal DA hearts were subjected to different cold ischemia times with or without 45 minutes of additional warm ischemia. The role of I/R was studied by harvesting syngrafts at different time points after reperfusion. Real-time reverse-transcriptase polymerase chain reaction quantified total HIF-1 mRNA, while enzyme-linked immunosorbent assay and immunohistochemistry quantified and localized HIF-1 protein. Our results show that HIF-1 nuclear immunoreactivity is increased during graft preservation and I/R leads to loss of nuclear HIF-1 immunoreactivity. Acute rejection induced HIF-1 in mRNA level. Our findings thus indicated that HIF-1 is activated during transplantation and suggested that manipulation of the HIF-1 pathway might reveal new therapeutic options to manage CAV.
Keränen
M A I
MA
Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Nykänen
A I
AI
Krebs
R
R
Tuuminen
R
R
Sandelin
H
H
Koskinen
P K
PK
Lemström
K B
KB
D000818:Animals; D015687:Cell Hypoxia; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000503:physiopathology*; D016027:Heart Transplantation / Q000276:immunology / Q000502:physiology*; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics*; D007150:Immunohistochemistry; D009926:Organ Preservation; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D051793:Hypoxia-Inducible Factor 1