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Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated

Henryk Dreger1, Kera Westphal, Andrea Weller

  • 1Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charité-Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany.

Cardiovascular Research
|April 9, 2009
PubMed
Abstract

Insights

Non-toxic proteasome inhibition upregulates antioxidant enzymes via the Nrf2 pathway, offering protection to heart cells from oxidative stress.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • The ubiquitin-proteasome system's role in cellular defense against oxidative stress is established.
  • Non-toxic proteasome inhibition previously demonstrated to upregulate antioxidative mechanisms.

Purpose of the Study:

  • To investigate if induced antioxidative enzymes contribute to cardioprotection from non-toxic proteasome inhibition.
  • To elucidate the molecular mechanisms underlying proteasome inhibitor-induced cardioprotection.

Main Methods:

  • Treatment of neonatal rat cardiac myocytes with MG132 (a proteasome inhibitor).
  • Assessment of cell viability and reactive oxygen species levels.
  • Analysis of antioxidative enzyme expression (SOD1, catalase, heme oxygenase 1) via immunoblots.
  • Luciferase reporter assays to study gene transcription.
  • Experiments using Nrf2 knockout mice to determine the role of Nrf2.

Main Results:

  • Non-toxic MG132 treatment protected cardiac myocytes against hydrogen peroxide-induced oxidative stress.
  • Proteasome inhibition led to the upregulation of key antioxidative enzymes, including superoxide dismutase 1 (SOD1).
  • Transcriptional activation of SOD1 was mediated by an antioxidant response element (ARE) and required the transcription factor Nrf2.

Conclusions:

  • Non-toxic proteasome inhibition confers cardioprotection.
  • This protection is mediated by the upregulation of antioxidative enzymes.
  • The Nrf2-dependent transcriptional activation of AREs is the key mechanism involved.

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