Beclin-1-Dependent Autophagy Protects the Heart During Sepsis Academic Article uri icon

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.

altmetric score

  • 49.85

author list (cited authors)

  • Sun, Y., Yao, X., Zhang, Q., Zhu, M., Liu, Z., Ci, B. o., ... Zang, Q. S.

citation count

  • 137

complete list of authors

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

publication date

  • May 2018