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Resveratrol protects against 4-hydroxynonenal-induced apoptosis by blocking JNK and c-JUN/AP-1 signaling

Ozgur Kutuk1, Giuseppe Poli, Huveyda Basaga

  • 1Biological Sciences and Bioengineering Program, Sabanci University, 34956 Orhanli, Tuzla Istanbul, Turkey.

Toxicological Sciences : an Official Journal of the Society of Toxicology
|December 3, 2005
PubMed

Insights

Resveratrol protects 3T3 fibroblasts from 4-hydroxynonenal (HNE)-induced apoptosis by inhibiting the JNK-c-Jun/AP-1 pathway. This study reveals resveratrol

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • 4-hydroxynonenal (HNE) is a toxic product of lipid peroxidation.
  • HNE induces apoptosis in cells through complex signaling pathways.

Purpose of the Study:

  • To investigate the protective effects of resveratrol against HNE-induced apoptosis in 3T3 fibroblasts.
  • To elucidate the specific signal transduction pathways involved in HNE-induced apoptosis and resveratrol's mechanism of action.

Main Methods:

  • 3T3 fibroblasts were exposed to HNE with or without resveratrol pretreatment.
  • MAP kinase (JNK, p38, ERK) and caspase activation pathways were analyzed.
  • Cytochrome c release, AP-1, c-Jun, phospho-c-Jun, and Nrf2 levels were assessed.
  • Dominant-negative c-Jun and JNK1 were overexpressed to confirm pathway involvement.

Main Results:

  • HNE induced apoptosis by activating JNK and p38, downregulating ERK, and triggering caspase activation and cytochrome c release.
  • Resveratrol effectively inhibited HNE-induced JNK and caspase activation, preventing apoptosis.
  • Resveratrol blocked HNE-induced AP-1 activation and Nrf2 downregulation.
  • Overexpression of dominant-negative c-Jun and JNK1 confirmed the critical role of the JNK-c-Jun/AP-1 pathway in HNE-induced apoptosis.

Conclusions:

  • Resveratrol protects against HNE-induced apoptosis, primarily by inhibiting the JNK-c-Jun/AP-1 signaling pathway.
  • These findings suggest a role for resveratrol in modulating MAP kinase pathways beyond its antioxidant properties.
  • Resveratrol's mechanism involves interfering with the cellular response to lipid peroxidation products via JNK signaling.

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