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Ask(1) and you shall receive: A new link between antioxidants and cell death signaling
Author(s) -
Czaja Mark J.
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510380132
Subject(s) - hepatoprotection , apoptosis , microbiology and biotechnology , ask1 , p38 mitogen activated protein kinases , caspase , viability assay , programmed cell death , xiap , chemistry , biology , kinase , biochemistry , protein kinase a , enzyme , cyclin dependent kinase 2 , glutathione
Hepatoprotection mediated by free radical scavenging molecules such as dimethyl sulfoxide (Me 2 SO) arose the question as to whether this effect involved one or several anti‐apoptotic signals. Here, using primary cultures of rat hepatocytes and in vivo thioacetamide‐induced liver failure, we showed that Me 2 SO failed to prevent any cleavage of initiator caspase‐8 and ‐9 but constantly inhibited procaspase‐3 maturation and apoptosis execution, pointing to an efficient inhibition of cleaved initiator caspase activities. Evidence was recently provided that apoptosis might require both caspase and ASK1/JNK‐p38 activities. We demonstrated that this kinase pathway was strongly inhibited in the presence of Me 2 SO whereas overexpression of ASK1 was able to restore caspase‐3 activity and apoptosis. Interestingly, we also found that GST M1/2 and GST A1/2 dropped under apoptotic conditions; furthermore transfection of GST M1, A1, or P1 to cells overexpressing ASK1, abolished caspase‐3 activity and restored viability. This role of GSTs was further assessed by showing that their high expression level was tightly associated with inhibition of ASK1 activity in Me 2 SO‐protected hepatocytes. Together, these results demonstrate that Me 2 SO‐mediated hepatoprotection involves a dual inhibition of cleaved initiator caspase and ASK1/JNK‐p38 activities. Furthermore, in highlighting the control of apoptosis by GSTs, these data provide new insights for analyzing the complex mechanisms of hepatoprotection.