We investigate here the role of
reactive oxygen species and
nitric oxide in
iron-induced cardiomyocyte
hypertrophy or cell death. Cultured rat cardiomyocytes incubated with 20 microM
iron (added as
FeCl(3)-Na nitrilotriacetate,
Fe-NTA) displayed
hypertrophy features that included increased
protein synthesis and cell size, plus realignment of
F-actin filaments along with sarcomeres and activation of the
atrial natriuretic factor gene promoter. Incubation with higher
Fe-NTA concentrations (100 microM) produced cardiomyocyte death by
necrosis. Incubation for 24 h with
Fe-NTA (20-40 microM) or the
nitric oxide donor Delta-nonoate increased iNOS
mRNA but decreased iNOS
protein levels; under these conditions,
iron stimulated the activity and the dimerization of iNOS.
Fe-NTA (20 microM) promoted short- and long-term generation of
reactive oxygen species, whereas preincubation with
l-arginine suppressed this response. Preincubation with 20 microM
Fe-NTA also attenuated the necrotic cell death triggered by 100 microM
Fe-NTA, suggesting that these preincubation conditions have cardioprotective effects. Inhibition of iNOS activity with
1400 W enhanced
iron-induced ROS generation and prevented both
iron-dependent cardiomyocyte
hypertrophy and cardioprotection. In conclusion, we propose that
Fe-NTA (20 microM) stimulates iNOS activity and that the enhanced NO production, by promoting
hypertrophy and enhancing survival mechanisms through ROS reduction, is beneficial to cardiomyocytes. At higher concentrations, however,
iron triggers cardiomyocyte death by
necrosis.