Yuxiao Sun1, Xiao Yao1, Qing-Jun Zhang2, Min Zhu2, Zhi-Ping Liu2, Bo Ci3, Yang Xie3, Deborah Carlson1, Beverly A Rothermel2, Yuxiang Sun4, Beth Levine5, Joseph A Hill2, Steven E Wolf1, Joseph P Minei1, Qun S Zang1. 1. Departments of Surgery (Y.S., X.Y., D.C., S.E.W., J.P.M., Q.S.Z.), University of Texas Southwestern Medical Center, Dallas. 2. Internal Medicine, Cardiology Division (Q.-J.Z., M.Z., Z.-P.L., B.A.R., J.A.H.), University of Texas Southwestern Medical Center, Dallas. 3. Clinical Science, Quantitative Biomedical Research Center (B.C., Y.X.), University of Texas Southwestern Medical Center, Dallas. 4. Department of Nutrition and Food Science, Texas A&M University, College Station (Y.S.). 5. Internal Medicine, Center for Autophagy Research, Howard Hughes Medical Institute (B.L.), University of Texas Southwestern Medical Center, Dallas.
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.
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.
Authors: S Michiorri; V Gelmetti; E Giarda; F Lombardi; F Romano; R Marongiu; S Nerini-Molteni; P Sale; R Vago; G Arena; L Torosantucci; L Cassina; M A Russo; B Dallapiccola; E M Valente; G Casari Journal: Cell Death Differ Date: 2010-01-08 Impact factor: 15.828
Authors: Qun S Zang; David L Maass; Jane G Wigginton; Robert C Barber; Bobbie Martinez; Ahamed H Idris; Jureta W Horton; Fiemu E Nwariaku Journal: Am J Physiol Heart Circ Physiol Date: 2010-03-26 Impact factor: 4.733
Authors: Qun S Zang; Bobbie Martinez; Xiao Yao; David L Maass; Lisha Ma; Steven E Wolf; Joseph P Minei Journal: PLoS One Date: 2012-08-27 Impact factor: 3.240
Authors: Anthony Orvedahl; Michael R McAllaster; Amy Sansone; Bria F Dunlap; Chandni Desai; Ya-Ting Wang; Dale R Balce; Cliff J Luke; Sanghyun Lee; Robert C Orchard; Maxim N Artyomov; Scott A Handley; John G Doench; Gary A Silverman; Herbert W Virgin Journal: Proc Natl Acad Sci U S A Date: 2019-07-25 Impact factor: 11.205
Authors: Leroy C Joseph; Michael V Reyes; Kundanika R Lakkadi; Blake H Gowen; Gyorgy Hasko; Konstantinos Drosatos; John P Morrow Journal: Am J Physiol Heart Circ Physiol Date: 2020-03-06 Impact factor: 4.733