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Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy.

Publication ,  Journal Article
Tannous, P; Zhu, H; Nemchenko, A; Berry, JM; Johnstone, JL; Shelton, JM; Miller, FJ; Rothermel, BA; Hill, JA
Published in: Circulation
June 17, 2008

BACKGROUND: Recent reports demonstrate that multiple forms of cardiovascular stress, including pressure overload, chronic ischemia, and infarction-reperfusion injury, provoke an increase in autophagic activity in cardiomyocytes. However, nothing is known regarding molecular events that stimulate autophagic activity in stressed myocardium. Because autophagy is a highly conserved process through which damaged proteins and organelles can be degraded, we hypothesized that stress-induced protein aggregation is a proximal trigger of cardiomyocyte autophagy. METHODS AND RESULTS: Here, we report that pressure overload promotes accumulation of ubiquitinated protein aggregates in the left ventricle, development of aggresome-like structures, and a corresponding induction of autophagy. To test for causal links, we induced protein accumulation in cultured cardiomyocytes by inhibiting proteasome activity, finding that aggregation of polyubiquitinated proteins was sufficient to induce cardiomyocyte autophagy. Furthermore, attenuation of autophagic activity dramatically enhanced both aggresome size and abundance, consistent with a role for autophagic activity in protein aggregate clearance. CONCLUSIONS: We conclude that protein aggregation is a proximal trigger of cardiomyocyte autophagy and that autophagic activity functions to attenuate aggregate/aggresome formation in heart. Findings reported here are the first to demonstrate that protein aggregation occurs in response to hemodynamic stress, situating pressure-overload heart disease in the category of proteinopathies.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

June 17, 2008

Volume

117

Issue

24

Start / End Page

3070 / 3078

Location

United States

Related Subject Headings

  • Ventricular Function
  • Ubiquitin
  • Transfection
  • Rats, Sprague-Dawley
  • Rats
  • Proteins
  • Pressure
  • Myocytes, Cardiac
  • Mice, Inbred C57BL
  • Mice
 

Citation

APA
Chicago
ICMJE
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Tannous, P., Zhu, H., Nemchenko, A., Berry, J. M., Johnstone, J. L., Shelton, J. M., … Hill, J. A. (2008). Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy. Circulation, 117(24), 3070–3078. https://doi.org/10.1161/CIRCULATIONAHA.107.763870
Tannous, Paul, Hongxin Zhu, Andriy Nemchenko, Jeff M. Berry, Janet L. Johnstone, John M. Shelton, Francis J. Miller, Beverly A. Rothermel, and Joseph A. Hill. “Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy.Circulation 117, no. 24 (June 17, 2008): 3070–78. https://doi.org/10.1161/CIRCULATIONAHA.107.763870.
Tannous P, Zhu H, Nemchenko A, Berry JM, Johnstone JL, Shelton JM, et al. Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy. Circulation. 2008 Jun 17;117(24):3070–8.
Tannous, Paul, et al. “Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy.Circulation, vol. 117, no. 24, June 2008, pp. 3070–78. Pubmed, doi:10.1161/CIRCULATIONAHA.107.763870.
Tannous P, Zhu H, Nemchenko A, Berry JM, Johnstone JL, Shelton JM, Miller FJ, Rothermel BA, Hill JA. Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy. Circulation. 2008 Jun 17;117(24):3070–3078.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

June 17, 2008

Volume

117

Issue

24

Start / End Page

3070 / 3078

Location

United States

Related Subject Headings

  • Ventricular Function
  • Ubiquitin
  • Transfection
  • Rats, Sprague-Dawley
  • Rats
  • Proteins
  • Pressure
  • Myocytes, Cardiac
  • Mice, Inbred C57BL
  • Mice