Effects of FK506 on acute allograft rejection in transplanted rat heart: the role of mitogen-activated protein kinases, AP-1 and NF-kappaB.
To scrutinize the effect of the immunosuppressant on acute allograft rejection as related to the intracellular signal transduction, heterotopic cardiac transplantation was performed from DA rat to Lewis rat with/without FK506. In the experimental group, recipients were given FK506 intramuscularly for 5 days. The control group received placebo. Allograft survivals were compared between two groups. For the assay of mitogen-activated protein kinase (MAPKs) families, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) in the left ventricular free wall (LV) and septum (SEP) of the grafts, rats were sacrificed on POD 5 (n=5 in each group). Extracellular signal-regulated kinase (ERK) and p38MAPK were measured using Western blot analysis. AP-1 and NF-kappaB DNA binding activities were measured by electrophoretic mobility shift assay. FK506 prolonged allograft survival (6.5 vs 31 days), and suppressed activation of myocardial MAPKs (ERK: 66% in LV and 67% in SEP, p38MAPK: 62% in LV and 72% in SEP), AP-1 (24% in LV and 18% in SEP), and NF-kappaB (41% in LV and 20% in SEP) (the mean value of activities in the control group was represented as 100%). These results suggest that the signal transduction pathways may play important roles in acute allograft rejection in rat cardiac transplantation.
Aoyama
Takanobu
T
Second Department of Surgery, Osaka City University Medical School, Japan. m2645796@msic.med.osaka-cu.ac.jp
Suehiro
Shigefumi
S
Hirai
Hidekazu
H
Shibata
Toshihiko
T
Yoshiyama
Minoru
M
Omura
Takashi
T
Kim
Shokei
S
Kinoshita
Hiroaki
H
D000208:Acute Disease; D000818:Animals; D006084:Graft Rejection / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D020928:Mitogen-Activated Protein Kinases; D016559:Tacrolimus