Iron induces protection and necrosis in cultured cardiomyocytes: Role of reactive oxygen species and nitric oxide.
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.
Munoz
Juan Pablo
JP
Centro FONDAP de Estudios Moleculares de la Célula, Universidad de Chile, Santiago 838-0492, Chile . jpablo_munoz@yahoo.com
Chiong
Mario
M
García
Lorena
L
Troncoso
Rodrigo
R
Toro
Barbra
B
Pedrozo
Zully
Z
Diaz-Elizondo
Jessica
J
Salas
Daniela
D
Parra
Valentina
V
Núñez
Marco T
MT
Hidalgo
Cecilia
C
Lavandero
Sergio
S
D000818:Animals; D017209:Apoptosis; D001120:Arginine / Q000737:chemistry; D019281:Dimerization; D005609:Free Radicals; D015971:Gene Expression Regulation, Enzymologic; D006984:Hypertrophy; D007501:Iron / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009336:Necrosis; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species
D005609:Free Radicals; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D001120:Arginine; D007501:Iron; D052247:Nitric Oxide Synthase Type II