Fas-mediated apoptosis in Adriamycin-induced cardiomyopathy in rats - In vivo study

Background-The precise molecular mechanism of Adriamycin-induced cardiomyop athy (ADR-CM) is still unknown. We address the demonstration of apoptotic m yocardial cell death and the apoptosis-inducing molecules in ADR-CM induced in rats. Methods and Results-Until 8 weeks after the first administration of ADR, th ere was no increase in the number of labeled cells by terminal deoxynucleot idyl transferase assay (TUNEL method). Apoptotic indices increased signific antly at weeks 9 and 10 in hearts of the ADR-trrated group hut not in those of the control group (0.42+0.12% versus 0.10+/-0.02% and 0.86+/-0.11% vers us 0.09+/-0.04% at weeks 9 and 10, respectively). DNA ladder formation was also observed in the myocardial tissues during the late stages of the ADR-C M of rats. There was no significant difference in expression of p53 gene be tween the ADR group and the control group at either the message or the prot ein level. An overexpression of Fas antigen was shown in myocardial cells o f ADR-treated hearts at weeks 9 and 10 by both Western blotting and immunof luorescent staining. Furthermore, we confirmed that neutralization of anti- Fas ligand antibody inhibited ADR-induced apoptosis. Conclusions-Apoptotic cell death was observed in the hearts of ADR-CM rats, and the number of apoptotic myocardial cells increased with the deteriorat ion of morphological findings and cardiac function, indicating that apoptos is may be an important mechanism of loss of myocardial cells and cardiac dy sfunction in ADR-CM. Apoptosis in ADR-CM rats is not p53-dependent but rath er is executed through a Fas-mediated pathway.