Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy

Paul Tannous, Hongxin Zhu, Andriy Nemchenko, Jeff M. Berry, Janet L. Johnstone, John M. Shelton, Francis J. Miller, Beverly A. Rothermel, Joseph A. Hill

Research output: Contribution to journalArticle

157 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3070-3078
Number of pages9
JournalCirculation
Volume117
Issue number24
DOIs
StatePublished - Jun 17 2008

Fingerprint

Autophagy
Cardiac Myocytes
Proteins
Pressure
Ubiquitinated Proteins
Proteasome Endopeptidase Complex
Heat-Shock Proteins
Reperfusion Injury
Organelles
Infarction
Heart Ventricles
Heart Diseases
Myocardium
Hemodynamics
Protein Aggregates

Keywords

  • Autophagy
  • Heart failure
  • Hypertrophy
  • Protein aggregation
  • Remodeling

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine
  • Physiology

Cite this

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 ; Zhu, Hongxin ; Nemchenko, Andriy ; Berry, Jeff M. ; Johnstone, Janet L. ; Shelton, John M. ; Miller, Francis J. ; Rothermel, Beverly A. ; Hill, Joseph A. / Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy. In: Circulation. 2008 ; Vol. 117, No. 24. pp. 3070-3078.
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Tannous, P, Zhu, H, Nemchenko, A, Berry, JM, Johnstone, JL, Shelton, JM, Miller, FJ, Rothermel, BA & Hill, JA 2008, 'Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy', Circulation, vol. 117, no. 24, pp. 3070-3078. https://doi.org/10.1161/CIRCULATIONAHA.107.763870

Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy. / Tannous, Paul; Zhu, Hongxin; Nemchenko, Andriy; Berry, Jeff M.; Johnstone, Janet L.; Shelton, John M.; Miller, Francis J.; Rothermel, Beverly A.; Hill, Joseph A.

In: Circulation, Vol. 117, No. 24, 17.06.2008, p. 3070-3078.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy

AU - Tannous, Paul

AU - Zhu, Hongxin

AU - Nemchenko, Andriy

AU - Berry, Jeff M.

AU - Johnstone, Janet L.

AU - Shelton, John M.

AU - Miller, Francis J.

AU - Rothermel, Beverly A.

AU - Hill, Joseph A.

PY - 2008/6/17

Y1 - 2008/6/17

N2 - 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.

AB - 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.

KW - Autophagy

KW - Heart failure

KW - Hypertrophy

KW - Protein aggregation

KW - Remodeling

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U2 - 10.1161/CIRCULATIONAHA.107.763870

DO - 10.1161/CIRCULATIONAHA.107.763870

M3 - Article

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