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- Abstract:
- Background: Glucagon-like peptide-1 (GLP-1) agonist Semaglutide reduces major adverse cardiovascular events and improves myocardial perfusion and ventricular performance, but the myocardial mechanisms underlying these benefits remain incompletely understood. We investigated whether semaglutide alters structural and molecular processes within chronically ischemic myocardium in a swine model of ischemic heart disease and metabolic syndrome. Methods: Sixteen Yorkshire swine with diet-induced metabolic syndrome underwent left circumflex (LCx) ameroid constrictor placement and received oral semaglutide (HSEM, n=8) or no treatment (HFC, n=8) for five weeks. Ischemic myocardium was analyzed using histology, immunohistochemistry, immunoblotting, and quantitative proteomics. Results: Semaglutide reduced interstitial myocardial fibrosis, vimentin, and SMAD family member 2/3 (SMAD2/3) expression. Myocardial 3-nitrotyrosine (3-NT) staining and nuclear factor erythroid 2–related factor 2 (NRF2) expression increased, indicating altered redox homeostasis and stress-response signaling. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) was unchanged, whereas cleaved caspase-3 decreased and microtubule-associated protein 1 light chain 3 alpha (LC3A) increased, consistent with altered apoptotic and autophagy-associated signaling. Inflammatory cell abundance was unchanged, whereas increased nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα) expression and broad proteomic alterations indicated modulation of inflammatory and immune-associated signaling. Proteomics further identified alterations in extracellular matrix (ECM) organization, focal adhesion, cytoskeletal architecture, mitochondrial metabolism, and protein homeostasis. Nonischemic myocardium demonstrated reduced nuclear factor kappa B (NF-κB) signaling and additional molecular alterations. Conclusions: Semaglutide induces coordinated structural and molecular changes in chronically ischemic myocardium characterized by reduced fibrosis and apoptotic signaling and alterations in redox, autophagy-associated, inflammatory, ECM, and cytoskeletal pathways. Together with previously demonstrated physiological and vascular improvements, these findings suggest that semaglutide modifies myocardial biology beyond its metabolic effects.
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Jad Hamze BS; Kelsey Muir MD; Clark Zheng MD; Dany Hamze; Keertana Yalamanchili BS; Ryan Meehan MD; Will Robinson MD; Regan Cavin; Himanshu Kaushik BS; Frank W. Sellke MD,
"GLP-1 Agonist Semaglutide Promotes Molecular and Structural Remodeling of Chronically Ischemic Myocardium"
(2026).
Warren Alpert Medical School Academic Symposium.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/9vkw-7e98
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Warren Alpert Medical School Academic Symposium
The Warren Alpert Medical School Academic Symposium is an annual event at Warren Alpert Medical School of Brown University that provides Year II medical students a venue to present their summer research in a poster format. Participation in the Symposium …...