Doxorubicin-Induced Cardiotoxicity Through SIRT1 Loss Potentiates Overproduction of Exosomes in Cardiomyocytes

Shuai Zhang1, Yu Yang1, Xinchen Lv1

  • 1Department of Forensic Medicine, School of Basic Medicine, Soochow University, Suzhou 215123, China.

Insights

Doxorubicin (DOX) increases cardiotoxicity by promoting exosome secretion from cardiomyocytes via reduced SIRT1 expression and impaired lysosomal acidification. Restoring SIRT1 alleviates DOX-induced cardiomyocyte injury.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cell Biology

Background:

  • Doxorubicin (DOX) induces cardiotoxicity, a significant clinical concern.
  • Cardiomyocyte injury is a key pathological feature of DOX-induced cardiomyopathy.
  • DOX-induced exosomes contribute to cardiotoxicity, but mechanisms of secretion regulation are unclear.

Purpose of the Study:

  • To elucidate the mechanisms by which DOX regulates exosome secretion from cardiomyocytes.
  • To investigate the role of SIRT1 and lysosomal acidification in DOX-induced cardiotoxicity.
  • To identify potential therapeutic targets for mitigating DOX cardiotoxicity.

Main Methods:

  • Investigated DOX effects on exosome secretion in cardiomyocytes.
  • Assessed the role of silencing information regulator 1 (SIRT1) and lysosomal acidification.
  • Utilized molecular biology techniques including gene overexpression and assessment of lysosomal function.
  • Examined the expression of ATP6V1A subunit of vacuolar-type H+ ATPase (V-ATPase).

Main Results:

  • DOX significantly increased exosome secretion from cardiomyocytes, exacerbating injury.
  • DOX reduced SIRT1 expression, impairing lysosomal acidification and multivesicular body (MVB) degradation.
  • SIRT1 loss decreased ATP6V1A expression, inhibiting V-ATPase function.
  • Overexpressing SIRT1 improved lysosomal acidification, reduced exosome secretion, and alleviated DOX cardiotoxicity.

Conclusions:

  • SIRT1-mediated impairment of lysosomal acidification is a key mechanism for increased DOX-induced exosome secretion.
  • Targeting SIRT1 and lysosomal acidification offers a novel therapeutic strategy for DOX cardiotoxicity.
  • DOX-induced mitochondrial-derived vesicles may also contribute to increased exosome release.