4-Hydroxynonenal signalling to apoptosis in isolated rat hepatocytes: the role of PKC-delta.
4-Hydroxynonenal, a significant aldehyde end product of membrane lipid peroxidation with numerous biochemical activities, has consistently been detected in various human diseases. Concentrations actually detectable in vivo (0.1-5 microM) have been shown to up-regulate different genes and modulate various enzyme activities. In connection with the latter aspect, we show here that, in isolated rat hepatocytes, 1 microM 4-hydroxynonenal selectively activates protein kinase C-delta, involved in apoptosis of many cell types; it also induces very early activation of Jun N-terminal kinase, in parallel increasing activator protein-1 DNA-binding activity in a time-dependent manner and triggering apoptosis after only 120 min treatment. These phenomena are likely protein kinase C-delta-dependent, being significantly reduced or annulled by cell co-treatment with rottlerin, a selective inhibitor of protein kinase C-delta. We suggest that 4-hydroxynonenal may induce apoptosis through activation of protein kinase C-delta and of Jun N-terminal kinase, and consequent up-regulation of activator protein-1 DNA binding.
Castello
L
L
Department of Clinical and Biological Sciences, University of Torino, Regione Gonzole 10, 10043 Orbassano (TO), Italy.
Marengo
B
B
Nitti
M
M
Froio
T
T
Domenicotti
C
C
Biasi
F
F
Leonarduzzi
G
G
Pronzato
M A
MA
Marinari
U M
UM
Poli
G
G
Chiarpotto
E
E
D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000447:Aldehydes; D018808:Transcription Factor AP-1; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione; C027576:4-hydroxy-2-nonenal