title: 4-Hydroxynonenal signalling to apoptosis in isolated rat hepatocytes: the role of PKC-delta.
abstract: 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.
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Regione Gonzole 10, 10043 Orbassano (TO), Italy.
authors.forename: L
authors.initials: L
authors.lastname: Castello
authors.forename: B
authors.initials: B
authors.lastname: Marengo
authors.forename: M
authors.initials: M
authors.lastname: Nitti
authors.forename: T
authors.initials: T
authors.lastname: Froio
authors.forename: C
authors.initials: C
authors.lastname: Domenicotti
authors.forename: F
authors.initials: F
authors.lastname: Biasi
authors.forename: G
authors.initials: G
authors.lastname: Leonarduzzi
authors.forename: M A
authors.initials: MA
authors.lastname: Pronzato
authors.forename: U M
authors.initials: UM
authors.lastname: Marinari
authors.forename: G
authors.initials: G
authors.lastname: Poli
authors.forename: E
authors.initials: E
authors.lastname: Chiarpotto
mesh_terms: 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
chemical_list: 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