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 L Carlson, Beverly A Rothermel, Yuxiang Sun, Beth Levine, Joseph A Hill, Steven E. Wolf, Joseph P Minei, Qun Zang

Research output: Contribution to journalArticle

37 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

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Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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