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Published on: July 13, 2018
Age-Independent Cardiac Protection by Pharmacological Activation of Beclin-1 During Endotoxemia and Its Association
Matthew Kim1, Azadeh Nikouee1, Raymond Zou2
1Department of Surgery, Burn & Shock Trauma Research Institute Loyola University Chicago Stritch School of Medicine Maywood IL.
Abstract:
Background We showed that Beclin-1-dependent autophagy protects the heart in young and adult mice that underwent endotoxemia. 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, attenuated cytokines, and improved cardiac performance in both young and aged mice during endotoxemia. A targeted metabolomics 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.
Insights
TB-peptide activates autophagy to protect the heart during endotoxemia in young and aged mice. This peptide improves cardiac function and metabolism, offering therapeutic potential for sepsis-induced cardiomyopathy.
Area of Science:
- Cardiovascular Science
- Autophagy Research
- Metabolomics
Background:
- Beclin-1-dependent autophagy protects the heart during endotoxemia.
- The therapeutic potential of Beclin-1 activating peptide (TB-peptide) in endotoxemia needs further investigation, particularly in aged populations.
- Lipopolysaccharide (LPS) challenge induces cardiac dysfunction and metabolic alterations.
Purpose of the Study:
- To compare the therapeutic effects of TB-peptide on endotoxemia-induced cardiac outcomes in young adult and aged mice.
- To evaluate LPS-induced and TB-peptide treatment-mediated alterations in myocardial metabolism.
- To assess the impact of TB-peptide on autophagy and cytokine levels.
Main Methods:
- Young (10-week) and aged (24-month) C57BL/6J mice were challenged with LPS.
- Mice received TB-peptide or vehicle treatment.
- Cardiac function, circulating cytokines, myocardial autophagy, and myocardial metabolites (361 targeted) were evaluated.
Main Results:
- TB-peptide enhanced autophagy, reduced cytokines, and improved cardiac performance in both young and aged mice during endotoxemia.
- LPS impaired glucose and amino acid metabolism, which TB-peptide ameliorated in all age groups.
- Lipid metabolism showed age-dependent responses to LPS, with TB-peptide partially mitigating effects in young mice but not aged mice.
Conclusions:
- Pharmacological Beclin-1 activation via TB-peptide offers cardiac protection during endotoxemia in both young and aged individuals.
- TB-peptide demonstrates therapeutic potential for sepsis-induced cardiomyopathy.
- Age-independent protection by TB-peptide is linked to the reprogramming of energy production through glucose and amino acid metabolism.
