W. Takahashi et al., Inducible nitric oxide-mediated myocardial apoptosis contributes to graft failure during acute cardiac allograft rejection in mice, JPN HEART J, 41(4), 2000, pp. 493-506
The mechanism through which nitric oxide (NO) mediates cardiac myocyte deat
h during acute cardiac rejection has not been fully delineated. We sought t
o determine whether NO promotes myocardial apoptosis and contributes to gra
ft failure during acute cardiac rejection in a murine model.
Heterotopic cardiac transplantation was performed from Balb / c (H-2(d)) to
C3H / He mice (H-2(k)). Recipients were treated with aminoguanidine (AG) a
t 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 surv
ival, histological changes and serum NO levels were assessed. Intra-graft a
poptosis was evaluated using a DNA fragmentation detection assay (TUNEL met
hod) and DNA laddering.
Significant prolongation of graft survival was observed in allografts treat
ed 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 tha
t of the apoptotic infiltrating cells. DNA laddering was clearly detected i
n nontreated allografts but was suppressed in AG-treated allografts.
Inhibition of NO production by AG prolonged murine cardiac allograft surviv
al. The decrease in intra-graft apoptotic activity paralleled histological
improvement. Cardiac myocyte death which occurs through an apoptotic proces
s mediated by NO contributes to graft failure during acute cardiac rejectio
n.