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ToxSci Advance Access originally published online on December 1, 2005
Toxicological Sciences 2006 90(1):120-132; doi:10.1093/toxsci/kfj055
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Resveratrol Protects Against 4-Hydroxynonenal-Induced Apoptosis by Blocking JNK and c-JUN/AP-1 Signaling

Ozgur Kutuk*, Giuseppe Poli{dagger} and Huveyda Basaga*,1

* Biological Sciences and Bioengineering Program, Sabanci University, 34956 Orhanli, Tuzla Istanbul, Turkey; and {dagger} Department of Clinical and Biological Sciences,University of Turin at St. Luigi Gonzaga Hospital 10043-Orbassano, Turin, Italy

Received July 1, 2005; accepted November 12, 2005

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 gain 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, and 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 an antioxidant-quenching reactive oxygen intermediate.

Key Words: 4-hydroxynonenal; lipid peroxidation; apoptosis; AP-1; MAP kinases; resveratrol.


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