NFκB promotes oxidative stress-induced necrosis and ischemia/reperfusion injury by inhibiting Nrf2-ARE pathway

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Xiaoyun Guo1, Siqi Hong1, Hui He1

  • 1Department of Physiology and Biophysics, University of Washington, Seattle, WA, 98195, USA.

Free Radical Biology & Medicine
|August 4, 2020
PubMed

Insights

Nuclear Factor kappa B (NFκB) promotes cell death during oxidative stress by suppressing antioxidant pathways. Inhibiting NFκB protects against heart injury and improves cardiac function after ischemia.

Area of Science:

  • Molecular Biology
  • Cardiovascular Research
  • Cell Death Mechanisms

Background:

  • Oxidative stress is a key factor in cell death and organ injury, particularly in the heart.
  • Nuclear Factor kappa B (NFκB) is a transcription factor typically associated with inflammation and survival, but its role in oxidative stress-induced cell death is complex.
  • The Nrf2-ARE pathway is crucial for cellular defense against oxidative damage.

Purpose of the Study:

  • To investigate the role of NFκB in oxidative stress-induced necrosis.
  • To elucidate the mechanism by which NFκB influences antioxidant signaling.
  • To evaluate the therapeutic potential of targeting NFκB in cardiac ischemic injury.

Main Methods:

  • Utilized genetic manipulation (e.g., NFκB-p65 inactivation, cardiomyocyte-specific deletion) and pharmacological inhibitors (e.g., BMS-345541, trichostatin A).
  • Assessed cell death, HMGB1 release, and NFκB-luciferase activity in cardiomyocytes under simulated ischemia/reperfusion (sI/R) and doxorubicin (DOX) treatment.
  • Investigated protein interactions (co-immunoprecipitation) and transcriptional activity of Nrf2-ARE.
  • Evaluated myocardial infarct size, cardiac remodeling, and functional recovery in vivo after ischemia/reperfusion (I/R) injury.

Main Results:

  • NFκB activation promoted, while its inactivation inhibited, oxidative stress-induced cell death and HMGB1 release.
  • NFκB suppressed Nrf2-ARE antioxidant signaling and reduced the expression of antioxidant proteins via transcriptional silencing, dependent on HDAC3 interaction.
  • Inhibition of NFκB or HDAC3 enhanced Nrf2-ARE activity and promoted cell survival post-sI/R.
  • Cardiomyocyte-specific deletion of NFκB-p65 attenuated myocardial infarct size and improved cardiac function and remodeling after I/R injury.

Conclusions:

  • NFκB acts as a pro-cell death factor in oxidative stress-induced necrosis by suppressing the Nrf2-ARE antioxidant pathway through an HDAC3-dependent mechanism.
  • Targeting NFκB represents a novel therapeutic strategy for mitigating cardiac ischemic injury and pathological remodeling.
Keywords:
HDAC3Ischemia/reperfusion injuryNFκBNecrosisNrf2Oxidative stress

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