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TAK1 activates AMPK-dependent cell death pathway in hydrogen peroxide-treated cardiomyocytes, inhibited by heat shock

Zhiyu Chen1, Xiaolu Shen, Fengyan Shen

  • 1Division of Anesthesia and Critical Care Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Yangpu District, Shanghai, China.

Molecular and Cellular Biochemistry
|February 5, 2013
PubMed

Insights

AMP-activated protein kinase (AMPK) activation by hydrogen peroxide (H2O2) promotes cardiomyocyte death. Transforming growth factor-β-activating kinase 1 (TAK1) activates AMPK, while heat shock protein-70 (HSP-70) mitigates this pathway.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Oxidative Stress Research

Background:

  • Hydrogen peroxide (H2O2) induces cardiomyocyte death through oxidative stress.
  • AMP-activated protein kinase (AMPK) is a key cellular energy sensor.
  • The precise mechanisms of AMPK activation by H2O2 in cardiomyocytes remain unclear.

Purpose of the Study:

  • To investigate the role of AMPK in H2O2-induced cardiomyocyte death.
  • To elucidate the signaling pathways upstream of AMPK activation by H2O2.
  • To explore the protective effects of heat shock protein-70 (HSP-70) in this context.

Main Methods:

  • Utilized primary cardiomyocytes and H9c2 cell lines.
  • Administered H2O2 to induce oxidative stress and cell death.
  • Employed AMPK inhibitors and RNA interference (RNAi) to block AMPK activity.
  • Investigated the role of transforming growth factor-β-activating kinase 1 (TAK1) as an upstream activator.
  • Assessed the impact of HSP-70 on reactive oxygen species (ROS) accumulation and signaling pathway activation.

Main Results:

  • Significant AMPK activation was observed in H2O2-treated cardiomyocytes.
  • Inhibition of AMPK reduced H2O2-induced cardiomyocyte death.
  • H2O2 induced TAK1 activation, which subsequently activated AMPK.
  • TAK1 inhibition suppressed H2O2-induced AMPK activation and cell death.
  • Over-expression of TAK1 enhanced AMPK activation and cardiomyocyte death.
  • HSP-70 reduced ROS accumulation, thereby inhibiting TAK1/AMPK activation and cardiomyocyte death.

Conclusions:

  • TAK1 activates an AMPK-dependent cell death pathway in H2O2-treated cardiomyocytes.
  • HSP-70 exerts a protective effect by reducing ROS and inhibiting the TAK1/AMPK signaling cascade.
  • Targeting the TAK1/AMPK pathway may offer therapeutic strategies for conditions involving oxidative stress-induced heart damage.

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