Abstract
Purpose Diastolic dysfunction is an increasingly common cardiac pathology linked to heart failure with preserved ejection fraction. Previous studies have implicated glucagon-like peptide 1 (GLP-1) receptor agonists as potential therapies for improving diastolic dysfunction. In this study, we investigate the physiologic and metabolic changes in a mouse model of angiotensin II (AngII) mediated diastolic dysfunction with and without the GLP-1 receptor agonist liraglutide (Lira).
Methods Mice were divided into sham, AngII, or AngII + Lira therapy for 4 weeks. Mice were monitored for cardiac function, weight change, and blood pressure at baseline and after 4 weeks of treatment. After 4 weeks of treatment, tissue was collected for histology, protein analysis, targeted metabolomics, and protein synthesis assays.
Results AngII treatment causes diastolic dysfunction when compared to sham mice. Lira partially prevents this dysfunction. The improvement in function in Lira mice is associated with dramatic changes in amino acid accumulation in the heart. Lira mice also have improved markers of protein translation by Western blot and increased protein synthesis by puromycin assay, suggesting that increased protein turnover protects against fibrotic remodeling and diastolic dysfunction seen in the AngII cohort. Lira mice also lost lean muscle mass compared to the AngII cohort, raising concerns about peripheral muscle scavenging as a source of the increased amino acids in the heart.
Conclusions Lira therapy protects against AngII-mediated diastolic dysfunction, at least in part by promoting amino acid uptake and protein turnover in the heart. Liraglutide therapy is associated with loss of mean muscle mass, and long-term studies are warranted to investigate sarcopenia and frailty with liraglutide therapy in the setting of diastolic disease.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Updated Figures 2 to include additional measures of hypertrophy, rearranged Figure 3 and supplemental Figures 2-4, and added text to manuscript to reflect clinical relevance.
Abbreviations
- 4EBP1
- Eukaryotic translation initiation factor 4E-binding protein 1
- AngII
- Angiotensin II
- ANOVA
- Analysis of variance
- ASM
- Acid soluble metabolites
- BCAA
- Branched-chain amino acids
- BCKDH
- Branched-chain α-keto acid dehydrogenase complex
- BP
- Blood pressure
- CPT1b
- Carnitine palmitoyltransferase 1B
- ECG
- Electrocardiogram
- EF
- Ejection Fraction
- ET
- Ejection Time
- FAO
- Fatty acid oxidation
- GAPDH
- Glyceraldehyde 3-Phosphate Dehydrogenase
- GLP-1
- Glucagon-like peptide 1
- Gluc 6p
- Glucose 6 phosphate
- Gly 3p
- Glyceraldehyde-3-phosphate
- HFpEF
- Heart failure with preserved ejection fraction
- H&E
- Hematoxylin and eosin
- IP
- Intraperitoneal
- IVCT
- Isovolumic contraction time
- IVRT
- Isovolumic relaxation time
- KCL
- Potassium Chloride
- LC-HRMS
- Liquid chromatography-high resolution mass spectrometry
- Lira
- liraglutide
- LV
- Left Ventricle
- MCAD
- Medium chain acyl-CoA dehydrogenase
- P62
- p62/Sequestosome 1
- Rib 5p
- Ribulose-5-phosphate
- rLSR
- Reverse longitudinal strain rate
- S6
- S6 Ribosomal Protein
- Sed 7p
- Seduheptulose 7-phosphate
- VLCAD
- Very long chain acyl-CoA dehydrogenase