Cyclic AMP prolongs graft survival by suppressing apoptosis and inflammatory gene expression in acute cardiac allograft rejection.
This study was designed to investigate the effects of cAMP on immune regulation and apoptosis during acute rat cardiac allograft rejection. We found that the production of immune markers such as inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), iNOS expression, and nitric oxide (NO) production, was significantly increased in the blood and transplanted hearts of allograft recipients, but not of isograft controls. These increases were effectively suppressed by the administration of the membrane permeable cAMP analog dibutyryl cAMP (db-cAMP). Administration of db-cAMP reduced allograft-induced elevation of several biochemical markers, such as adhesion molecule expression, iron-nitrosyl complex formation, caspase-3 activation, and apoptotic DNA fragmentation in an animal model. Furthermore, treatment of allograft recipients with db-cAMP prolonged median graft survival to 11 days compared with a median graft survival time of 8 days in saline-treated allograft recipients. These results suggest that db-cAMP exerts a beneficial effect on murine cardiac allograft survival by modulating allogeneic immune response and cytotoxicity.
Lee
Jie-Young
JY
Vascular System Research Center, School of Medicine, Kangwon National University, Chuncheon, Korea.
Kim
Jung Hwan
JH
Chae
Gibong
G
Lee
Bong-Ki
BK
Ha
Kwon-Soo
KS
Kwon
Young-Geun
YG
Kim
Young-Myeong
YM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use*; D004578:Electron Spin Resonance Spectroscopy; D006084:Graft Rejection / Q000188:drug therapy*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000009:adverse effects*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3