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Downregulation of Sirt1 as aging change in advanced heart failure

Tse-Min Lu, Jia-Yun Tsai, Yen-Chung Chen

  • 1National Yang-Ming University, Institute of Clinical Medicine, School of Medicine, Taipei, Taiwan. chiaopo@ms39.hinet.net.

Journal of Biomedical Science
|June 11, 2014
PubMed
Abstract

Insights

Low Sirtuin 1 (Sirt1) expression in advanced heart failure compromises cardiomyocyte survival. This down-regulation of Sirt1 contributes to increased cell death and oxidative stress, exacerbating heart failure progression.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cellular Aging

Background:

  • Congestive heart failure disrupts the balance between cardiomyocyte survival and death.
  • Sirtuin 1 (Sirt1) promotes cell survival and protects against injury in the heart.
  • The specific role of Sirt1 in human heart failure remains unclear.

Purpose of the Study:

  • To investigate the expression of Sirt1 and associated molecules in human cardiomyocytes from patients with advanced heart failure.
  • To elucidate the molecular mechanisms underlying cardiomyocyte dysfunction in heart failure.

Main Methods:

  • Quantification of Sirt1 expression in human heart failure samples versus healthy controls.
  • Analysis of downstream molecules involved in cell survival and apoptosis pathways.
  • Assessment of oxidative stress markers and cardiomyocyte death (TUNEL staining).

Main Results:

  • Significantly reduced Sirt1 expression (54.92%) in advanced heart failure cardiomyocytes.
  • Decreased expression of antioxidant enzymes (Mn-superoxide dismutase, thioredoxin1) and anti-apoptotic Bcl-xL.
  • Increased expression of pro-apoptotic Bax, elevated oxidative stress, and cardiomyocyte apoptosis.
  • Inhibition of the AMPK-Nampt-Sirt1 axis and impaired AMPK activation.
  • Evidence suggests p53 and FoxO1 pathways mediate Sirt1's effects on antioxidant and apoptotic molecule expression.

Conclusions:

  • Low Sirt1 expression in advanced heart failure contributes to reduced antioxidant capacity and increased apoptosis.
  • This down-regulation is linked to oxidative stress and dysregulation of p53 and FoxO1 pathways.
  • Sirt1 deficiency may be a key factor in heart failure pathogenesis, similar to aging processes.

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