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*

*Corresponding author for this work

Research output: Contribution to journalArticle

501 Scopus citations

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

ASJC Scopus subject areas

  • Medicine(all)

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    Zhu, H., Tannous, P., Johnstone, J. L., Kong, Y., Shelton, J. M., Richardson, J. A., Le, V., Levine, B., Rothermel, B. A., & Hill, J. A. (2007). Cardiac autophagy is a maladaptive response to hemodynamic stress. Journal of Clinical Investigation, 117(7), 1782-1793. https://doi.org/10.1172/JCI27523