Age-Independent Cardiac Protection by Pharmacological Activation of Beclin-1 During Endotoxemia and Its Association With Energy Metabolic Reprograming in Myocardium—A Targeted Metabolomics Study

Matthew Kim, Azadeh Nikouee, Raymond Zou, Di Ren, Zhibin He, Ji Li, Lu Wang, Danijel Djukovic, Daniel Raftery, Hayley Purcell, Daniel Promislow, Yuxiao Sun, Mohammad Goodarzi, Qing Jun Zhang, Zhi Ping Liu, Qun Zang

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: We showed that Beclin-1-dependent autophagy protects the heart in young and adult mice that underwent en-dotoxemia. Herein, we compared the potential therapeutic effects of Beclin-1 activating peptide, TB-peptide, on endotoxemia-induced cardiac outcomes in young adult and aged mice. We further evaluated lipopolysaccharide (lipopolysaccharide)-induced and TB-peptide treatment-mediated alterations in myocardial metabolism. METHODS AND RESULTS: C57BL/6J mice that were 10 weeks and 24 months old were challenged by lipopolysaccharide using doses at which cardiac dysfunction occurred. Following the treatment of TB-peptide or control vehicle, heart contractility, circulating cytokines, and myocardial autophagy were evaluated. We detected that TB-peptide boosted autophagy, attenu-ated cytokines, and improved cardiac performance in both young and aged mice during endotoxemia. A targeted metabo-lomics assay was designed to detect a pool of 361 known metabolites, of which 156 were detected in at least 1 of the heart tissue samples. Lipopolysaccharide-induced impairments were found in glucose and amino acid metabolisms in mice of all ages, and TB-peptide ameliorated these alterations. However, lipid metabolites were upregulated in the young group but moderately downregulated in the aged by lipopolysaccharide, suggesting an age-dependent response. TB-peptide mitigated lipopolysaccharide-mediated trend of lipids in the young mice but had little effect on the aged. (Study registration: Project DOI: https://doi.org/10.21228/M8K11W). CONCLUSIONS: Pharmacological activation of Beclin-1 by TB-peptide is cardiac protective in both young and aged population during endotoxemia, suggest a therapeutic potential for sepsis-induced cardiomyopathy. Metabolomics analysis suggests that an age-independent protection by TB-peptide is associated with reprograming of energy production via glucose and amino acid metabolisms.

Original languageEnglish (US)
Article numbere025310
JournalJournal of the American Heart Association
Volume11
Issue number14
DOIs
StatePublished - Jul 19 2022

Keywords

  • autophagy
  • Beclin-1
  • cardiac function
  • cardiac metabolism
  • endotoxemia
  • sepsis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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