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

26 Citations (Scopus)

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

Fingerprint

Autophagy
Sepsis
Lipopolysaccharides
Sirolimus
Mitochondrial Degradation
Inflammation
Beclin-1
Critical Care
Mitochondria
Fibrosis
Therapeutics
Phenotype
Peptides
Injections

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Beclin-1-Dependent Autophagy Protects the Heart During Sepsis. / Sun, Yuxiao; Yao, Xiao; Zhang, Qing Jun; Zhu, Min; Liu, Zhi-Ping; Ci, Bo; Xie, Yang; Carlson, Deborah L; Rothermel, Beverly A; Sun, Yuxiang; Levine, Beth; Hill, Joseph A; Wolf, Steven E.; Minei, Joseph P; Zang, Qun.

In: Circulation, Vol. 138, No. 20, 13.11.2018, p. 2247-2262.

Research output: Contribution to journalArticle

Sun, Yuxiao ; Yao, Xiao ; Zhang, Qing Jun ; Zhu, Min ; Liu, Zhi-Ping ; Ci, Bo ; Xie, Yang ; Carlson, Deborah L ; Rothermel, Beverly A ; Sun, Yuxiang ; Levine, Beth ; Hill, Joseph A ; Wolf, Steven E. ; Minei, Joseph P ; Zang, Qun. / Beclin-1-Dependent Autophagy Protects the Heart During Sepsis. In: Circulation. 2018 ; Vol. 138, No. 20. pp. 2247-2262.
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AU - Yao, Xiao

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AU - Zhu, Min

AU - Liu, Zhi-Ping

AU - Ci, Bo

AU - Xie, Yang

AU - Carlson, Deborah L

AU - Rothermel, Beverly A

AU - Sun, Yuxiang

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AU - Wolf, Steven E.

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