Cardiac autophagy is a maladaptive response to hemodynamic stress

Hongxin Zhu, Paul Tannous, Janet L. Johnstone, Yongli Kong, John M. Shelton, James A Richardson, Vien Le, Beth Levine, Beverly A Rothermel, Joseph A Hill

Research output: Contribution to journalArticle

461 Citations (Scopus)

Abstract

Cardiac hypertrophy is a major predictor of heart failure and a prevalent disorder with high mortality. Little is known, however, regarding mechanisms governing the transition from stable cardiac hypertrophy to decompensated heart failure. Here, we tested the role of autophagy, a conserved pathway mediating bulk degradation of long-lived proteins and cellular organelles that can lead to cell death. To quantify autophagic activity, we engineered a line of "autophagy reporter" mice and confirmed that cardiomyocyte autophagy can be induced by short-term nutrient deprivation in vivo. Pressure overload induced by aortic banding induced heart failure and greatly increased cardiac autophagy. Load-induced autophagic activity peaked at 48 hours and remained significantly elevated for at least 3 weeks. In addition, autophagic activity was not spatially homogeneous but rather was seen at particularly high levels in basal septum. Heterozygous disruption of the gene coding for Beclin 1, a protein required for early autophagosome formation, decreased cardiomyocyte autophagy and diminished pathological remodeling induced by severe pressure stress. Conversely, Beclin 1 overexpression heightened autophagic activity and accentuated pathological remodeling. Taken together, these findings implicate autophagy in the pathogenesis of load-induced heart failure and suggest it may be a target for novel therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)1782-1793
Number of pages12
JournalJournal of Clinical Investigation
Volume117
Issue number7
DOIs
StatePublished - Jul 2 2007

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Autophagy
Hemodynamics
Heart Failure
Cardiomegaly
Cardiac Myocytes
Pressure
Organelles
Cell Death
Food
Mortality
Genes
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cardiac autophagy is a maladaptive response to hemodynamic stress. / Zhu, Hongxin; Tannous, Paul; Johnstone, Janet L.; Kong, Yongli; Shelton, John M.; Richardson, James A; Le, Vien; Levine, Beth; Rothermel, Beverly A; Hill, Joseph A.

In: Journal of Clinical Investigation, Vol. 117, No. 7, 02.07.2007, p. 1782-1793.

Research output: Contribution to journalArticle

Zhu, Hongxin ; Tannous, Paul ; Johnstone, Janet L. ; Kong, Yongli ; Shelton, John M. ; Richardson, James A ; Le, Vien ; Levine, Beth ; Rothermel, Beverly A ; Hill, Joseph A. / Cardiac autophagy is a maladaptive response to hemodynamic stress. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 7. pp. 1782-1793.
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