1,3-Butanediol enhances autophagy via PI3K/Akt/FOXO3 pathway to ameliorate cardiac remodeling post-myocardial infarction.

Abstract

BACKGROUND: Myocardial infarction (MI) remains a leading cause of cardiovascular mortality. While ketone bodies show cardioprotective potential, their role in regulating cardiomyocyte autophagy post-MI is unclear. METHODS: A rat MI model was established and treated with 1,3-butanediol (1,3-BD, 10 mg/100 g/day), a ketone precursor. Cardiac structure and function were assessed alongside autophagy and apoptosis levels. In vitro, hypoxia-induced cardiomyocytes were treated with β-hydroxybutyrate (β-HB) and phosphatidylinositol 3-kinase (PI3K) inhibitor. Mechanisms were explored via transcriptomics/metabolomics and validated by immunoblotting. RESULTS: 1,3-BD treatment for 4 weeks significantly elevated serum β-HB, improved cardiac structure and function,and reduced cardiomyocyte apoptosis in MI rats, a finding corroborated in vitro where β-HB attenuated hypoxia-induced apoptosis in primary neonatal rat cardiomyocytes. The number of autophagic vesicles and LC3 fluorescence intensity in the infarct border zone decreased in the MI group compared with the control group, whereas 1,3-BD significantly increased autophagy levels in cardiomyocytes. In vitro, both β-HB and the PI3K inhibitor increased autophagy. However, the combination did not have an additional effect on regulating autophagy. Multi-omics analysis revealed 1,3-BD enriched the autophagy and PI3K-Akt-FOXO3 pathways. MI activated PI3K-Akt signaling and suppressed FOXO3, downregulating autophagy proteins (Atg7, Atg13, Beclin1, ULK1, LC3II/LC3I). 1,3-BD intervention reversed these changes. CONCLUSION: 1,3-BD improves post-MI cardiac remodeling by inhibiting cardiomyocyte apoptosis and enhancing autophagy, the latter mediated via suppression of the PI3K/Akt/FOXO3 pathway. Ketone supplementation represents a promising strategy against ischemic cardiomyopathy.