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Nrf2 Activation as a Protective Feedback to Limit Cell Death in High Glucose-Exposed Cardiomyocytes

Cheng-Yen Tsai1,2, Su-Ying Wen3,4, Shi-Yann Cheng5,6,7

  • 1Department of Pediatrics, China Medical University Beigang Hospital, Yunlin 651, Taiwan,ROC.

Journal of Cellular Biochemistry
|November 19, 2016
PubMed

Insights

High glucose activates the antioxidant Nrf2 pathway in heart cells via PKC and ROS signaling, protecting against diabetic cardiomyopathy. This pathway involves ROS, JNK, and p38, offering a potential therapeutic target.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cell Biology
  • Endocrinology

Background:

  • Hyperglycemia causes oxidative stress and diabetic cardiomyopathy.
  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key antioxidant transcription factor.
  • The signaling pathway linking high glucose to Nrf2 activation in cardiomyocytes is not fully understood.

Purpose of the Study:

  • To elucidate the signaling pathway regulating high glucose-induced Nrf2 activation in cardiomyocytes.
  • To investigate the role of protein kinase C (PKC) and reactive oxygen species (ROS) in this process.
  • To assess the protective effect of Nrf2 against high glucose-induced apoptosis in cardiac cells.

Main Methods:

  • Utilized high glucose (HG) treatment in cultured cardiomyocytes and streptozotocin (STZ)-induced diabetic rat models.
  • Employed small interfering RNAs (siRNAs) to knockdown specific proteins (p38, JNK, PKCα, PKCδ, Nrf2).
  • Assessed protein expression levels (Nrf2, cleaved-caspase3, Bcl2) and cellular events like apoptosis and nuclear translocation.

Main Results:

  • High glucose (33 mM) increased Nrf2 protein expression and nuclear translocation in cardiomyocytes.
  • PKCα/PKCδ activation, dependent on ROS production, mediated HG-induced JNK and p38 phosphorylation, leading to Nrf2 activation.
  • Nrf2 knockdown exacerbated HG-induced apoptosis, evidenced by increased cleaved-caspase3 and decreased Bcl2.
  • These signaling events were mirrored in the ventricles of STZ-induced diabetic rats.

Conclusions:

  • High glucose-induced cardiac Nrf2 activation is regulated by the PKCα/PKCδ-ROS-JNK/p38 signaling cascade.
  • Nrf2 activation plays a protective role against high glucose-induced oxidative stress and apoptosis in cardiomyocytes.
  • Targeting this pathway could offer a therapeutic strategy for diabetic cardiomyopathy.
Keywords:
HYPERGLYCEMIAMITOGEN-ACTIVATED PROTEIN KINASE (MAPK)NUCLEAR FACTOR E2-RELATED FACTOR 2 (Nrf2)PROTEIN KINASE C α/δ (PKCα/δ)REACTIVE OXYGEN SPECIES (ROS)

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