Liraglutide Protects Against Diastolic Dysfunction and Improves Ventricular Protein Translation

Cody Rutledge; Angela Enriquez; Kevin Redding; Mabel Lopez; Steven Mullett; Stacy L Gelhaus; Michael Jurczak; Eric Goetzman; Brett A Kaufman

doi:10.1007/s10557-023-07482-9

Liraglutide Protects Against Diastolic Dysfunction and Improves Ventricular Protein Translation

Cardiovasc Drugs Ther. 2023 Jun 29:10.1007/s10557-023-07482-9. doi: 10.1007/s10557-023-07482-9. Online ahead of print.

Authors

Cody Rutledge^{1

2}, Angela Enriquez^{1

2}, Kevin Redding², Mabel Lopez², Steven Mullett³, Stacy L Gelhaus³, Michael Jurczak⁴, Eric Goetzman⁵, Brett A Kaufman⁶

Affiliations

¹ Department of Medicine, Pittsburgh VA Medical Center, Pittsburgh, PA, USA.
² Division of Cardiology, Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
³ Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁵ Rangos Research Center, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Division of Cardiology, Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. bkauf@pitt.edu.

PMID: 37382868
PMCID: PMC10788853 (available on 2024-12-29)
DOI: 10.1007/s10557-023-07482-9

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.

Keywords: Amino acids; Diastolic dysfunction; Glucagon-like peptide receptor agonists; Liraglutide; Metabolism.

Abstract

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