ToxSci Advance Access published online on December 1, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj055
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1 Biological Sciences and Bioengineering Program, Sabanci University, 34956 Orhanli, Tuzla Istanbul, Turkey
* To whom correspondence should be addressed. In the present study we have studied the effect of resveratrol in signal transduction mechanisms leading to apoptosis in 3T3 fibroblasts when exposed to 4-hydroxynonenal (HNE). In order to get insight into the mechanisms of apoptotic response by HNE, we followed MAP kinase and caspase activation pathways; HNE induced early activation of JNK and p38 proteins but downregulated the basal activity of ERK 1/2. We were also able to demonstrate HNE-induced release of cytochrome c from mitochondria, caspase-9 and caspase-3 activation. Resveratrol effectively prevented HNE-induced JNK and caspase activation hence apoptosis. Activation of AP-1 along with increased c-Jun and phospho-c-Jun levels could be inhibited by pretreatment of cells with resveratrol. Moreover, Nrf2 downregulation by HNE could also be blocked by resveratrol. Overexpression of dominant negative c-Jun and JNK1 in 3T3 fibroblasts prevented HNE-induced apoptosis, which indicates a role for JNK-c-Jun/AP-1 pathway. In light of the JNK-dependent induction of c-Jun/AP-1 activation and the protective role of resveratrol, these data may show a critical potential role for JNK in the cellular response against toxic products of lipid peroxidation. In this respect resveratrol acting through MAP kinase pathways and specifically on JNK could have a role other than acting as antioxidant-quenching reactive oxygen intermediates.
Received July 1, 2005
Accepted November 12, 2005
In Vitro Toxicology
Resveratrol Protects against 4-Hydroxynonenal-Induced Apoptosis by Blocking JNK and c-Jun/AP-1 Signaling
Ozgur Kutuk 1,
Giuseppe Poli 2,
and
Huveyda Basaga 1 *
2 Department of Clinical and Biological Sciences, University of Turin at St. Luigi Gonzaga Hospital 10043-Orbassano, Turin, Italy
Huveyda Basaga, E-mail: huveyda{at}sabanciuniv.edu
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