Beclin-1-Dependent Autophagy Protects the Heart During Sepsis

Yuxiao Sun, Xiao Yao, Qing Jun Zhang, Min Zhu, Zhi Ping Liu, Bo Ci, Yang Xie, Deborah Carlson, Beverly A. Rothermel, Yuxiang Sun, Beth Levine, Joseph A. Hill, Steven Wolf, Joseph P. Minei, Qun S. Zang

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

BACKGROUND: Cardiac dysfunction is a major component of sepsis-induced multiorgan failure in critical care units. Changes in cardiac autophagy and its role during sepsis pathogenesis have not been clearly defined. Targeted autophagy-based therapeutic approaches for sepsis are not yet developed. METHODS: Beclin-1-dependent autophagy in the heart during sepsis and the potential therapeutic benefit of targeting this pathway were investigated in a mouse model of lipopolysaccharide (LPS)-induced sepsis. RESULTS: LPS induced a dose-dependent increase in autophagy at low doses, followed by a decline that was in conjunction with mammalian target of rapamycin activation at high doses. Cardiac-specific overexpression of Beclin-1 promoted autophagy, suppressed mammalian target of rapamycin signaling, improved cardiac function, and alleviated inflammation and fibrosis after LPS challenge. Haplosufficiency for beclin 1 resulted in opposite effects. Beclin-1 also protected mitochondria, reduced the release of mitochondrial danger-associated molecular patterns, and promoted mitophagy via PTEN-induced putative kinase 1-Parkin but not adaptor proteins in response to LPS. Injection of a cell-permeable Tat-Beclin-1 peptide to activate autophagy improved cardiac function, attenuated inflammation, and rescued the phenotypes caused by beclin 1 deficiency in LPS-challenged mice. CONCLUSIONS: These results suggest that Beclin-1 protects the heart during sepsis and that the targeted induction of Beclin-1 signaling may have important therapeutic potential.

Original languageEnglish (US)
Pages (from-to)2247-2262
Number of pages16
JournalCirculation
Volume138
Issue number20
DOIs
StatePublished - Nov 13 2018
Externally publishedYes

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Keywords

  • autophagy
  • Beclin-1
  • heart failure
  • mitochondrial degradation
  • sepsis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Sun, Y., Yao, X., Zhang, Q. J., Zhu, M., Liu, Z. P., Ci, B., Xie, Y., Carlson, D., Rothermel, B. A., Sun, Y., Levine, B., Hill, J. A., Wolf, S., Minei, J. P., & Zang, Q. S. (2018). Beclin-1-Dependent Autophagy Protects the Heart During Sepsis. Circulation, 138(20), 2247-2262. https://doi.org/10.1161/CIRCULATIONAHA.117.032821