Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy.

Full 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.

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Author information

Author/s: Tannous, Paul (P); Zhu, Hongxin (H); Nemchenko, Andriy (A); Berry, Jeff M (JM); Johnstone, Janet L (JL); Shelton, John M (JM); Miller, Francis J (FJ); Rothermel, Beverly A (BA); Hill, Joseph A (JA);

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

Grants: HL-006296 (Agency:United States NHLBI) ; HL-072016 (Agency:United States NHLBI) ; HL-075173 (Agency:United States NHLBI) ; HL-080144 (Agency:United States NHLBI)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Circulation (Circulation), published in United States. (Language: eng)

Reference: 2008-Jun; vol 117 (issue 24) : pp 3070-8

Dates: Created 2008/06/18; Completed 2008/08/01;

PMID: 18541737, status: MEDLINE (last retrieval date: 11/6/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Animals, Newborn
Autophagy
Cells, Cultured
Chymotrypsin - metabolism
Genes, Reporter
Heart Diseases - pathology; physiopathology
Heart Failure - etiology; physiopathology
Heart Ventricles - cytology; physiology
Male

Male
Mice
Mice, Inbred C57BL
Myocytes, Cardiac - cytology; physiology
Pressure
Proteins - chemistry; physiology
Rats
Rats, Sprague-Dawley
Transfection
Ubiquitin - metabolism

Associated Chemicals: Proteins (0) ; Ubiquitin (0) ; Chymotrypsin (EC 3.4.21.1)

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