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The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun

Nagalingam R Sundaresan1, Prabhakaran Vasudevan, Lei Zhong

  • 1Department of Surgery, Committee on Cellular and Molecular Physiology, University of Chicago, Chicago, IL, USA.

Nature Medicine
|October 23, 2012
PubMed

Insights

Sirtuin 6 (SIRT6) suppresses insulin-like growth factor (IGF)-Akt signaling, preventing cardiac hypertrophy and heart failure. Reduced SIRT6 expression is linked to human heart failure, highlighting its protective role.

Area of Science:

  • Cardiovascular Biology
  • Molecular Biology
  • Epigenetics

Background:

  • Abnormal insulin-like growth factor (IGF)-Akt signaling contributes to heart failure.
  • The precise molecular regulators of this pathway remain incompletely understood.

Purpose of the Study:

  • To investigate the role of sirtuin 6 (SIRT6) in regulating IGF-Akt signaling and cardiac hypertrophy.
  • To elucidate the molecular mechanisms by which SIRT6 influences cardiac function.

Main Methods:

  • Utilized SIRT6-deficient and transgenic mouse models.
  • Analyzed gene expression, protein interactions, and histone modifications (H3K9 acetylation).
  • Examined human failing heart tissue for SIRT6 expression.

Main Results:

  • SIRT6 deficiency led to cardiac hypertrophy and heart failure in mice.
  • SIRT6 transgenic mice showed protection against hypertrophic stimuli.
  • SIRT6 directly suppresses IGF-Akt signaling by binding gene promoters via c-Jun and H3K9 deacetylation.
  • Reduced SIRT6 expression was observed in human failing hearts.

Conclusions:

  • SIRT6 acts as a crucial negative regulator of IGF-Akt signaling and cardiac hypertrophy.
  • SIRT6 plays a protective role in preventing heart failure.
  • Findings reveal a novel link between SIRT6, IGF-Akt signaling, and cardiac disease pathogenesis.

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