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Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy

Paul Tannous1, Hongxin Zhu, Andriy Nemchenko

  • 1Department of Internal Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390-8573, USA.

Circulation
|June 11, 2008
PubMed

Insights

Protein aggregation triggers cardiomyocyte autophagy during heart stress. Autophagy helps clear these protein aggregates, preventing further damage in conditions like pressure-overload heart disease.

Area of Science:

  • Cardiovascular Biology
  • Cellular Stress Response
  • Molecular Cardiology

Background:

  • Cardiovascular stress, including pressure overload, ischemia, and infarction-reperfusion injury, increases autophagic activity in cardiomyocytes.
  • The molecular mechanisms stimulating autophagy in stressed myocardium remain largely unknown.
  • Autophagy degrades damaged proteins and organelles, a critical cellular housekeeping process.

Purpose of the Study:

  • To investigate whether stress-induced protein aggregation acts as a trigger for cardiomyocyte autophagy.
  • To explore the role of autophagy in managing protein aggregates in the stressed heart.

Main Methods:

  • Examined left ventricular tissue from pressure-overloaded hearts for protein aggregates and aggresome-like structures.
  • Utilized cultured cardiomyocytes to induce protein accumulation by inhibiting proteasome activity.
  • Assessed the impact of autophagy attenuation on aggresome formation and size.

Main Results:

  • Pressure overload led to the accumulation of ubiquitinated protein aggregates and aggresome-like structures in the heart.
  • Protein aggregation induced by proteasome inhibition in cultured cardiomyocytes was sufficient to trigger autophagy.
  • Reducing autophagic activity significantly increased aggresome size and abundance, indicating autophagy's role in clearance.

Conclusions:

  • Protein aggregation serves as a proximal trigger for cardiomyocyte autophagy in response to hemodynamic stress.
  • Autophagic activity plays a crucial role in mitigating the formation and accumulation of protein aggregates and aggresomes in the heart.
  • These findings establish a link between hemodynamic stress, protein aggregation, and autophagy, classifying pressure-overload heart disease within proteinopathies.
Abstract

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