Inducible nitric oxide-mediated myocardial apoptosis contributes to graft failure during acute cardiac allograft rejection in mice.
The mechanism through which nitric oxide (NO) mediates cardiac myocyte death during acute cardiac rejection has not been fully delineated. We sought to determine whether NO promotes myocardial apoptosis and contributes to graft failure during acute cardiac rejection in a murine model. Heterotopic cardiac transplantation was performed from Balb/c (H-2d) to C3H/He mice (H-2k). Recipients were treated with aminoguanidine (AG) at 400 mg/kg every day after surgery. As references, we used isografts in Balb/c mice with and without AG treatment (400 mg/kg/day). Graft survival, histological changes and serum NO levels were assessed. Intra-graft apoptosis was evaluated using a DNA fragmentation detection assay (TUNEL method) and DNA laddering. Significant prolongation of graft survival was observed in allografts treated with AG in comparison with nontreated allografts. Serum NO levels, which peaked on day 7 in nontreated allografts, were significantly decreased in AG-treated allografts. AG treatment decreased the number of apoptotic cells and lowered the ratio of the apoptotic cardiac myocytes in contrast to that of the apoptotic infiltrating cells. DNA laddering was clearly detected in nontreated allografts but was suppressed in AG-treated allografts. Inhibition of NO production by AG prolonged murine cardiac allograft survival. The decrease in intra-graft apoptotic activity paralleled histological improvement. Cardiac myocyte death which occurs through an apoptotic process mediated by NO contributes to graft failure during acute cardiac rejection.
Takahashi
W
W
Department of Internal Medicine, Shinshu University School of Medicine, Nagano, Japan.
Suzuki
J I
JI
Izawa
A
A
Takayama
K
K
Yamazaki
S
S
Isobe
M
M
D000818:Animals; D017209:Apoptosis; D006084:Graft Rejection; D006146:Guanidines / Q000494:pharmacology; D016027:Heart Transplantation; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009206:Myocardium / Q000473:pathology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
D006146:Guanidines; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C004479:pimagedine