Proteomic Profiling of GLP-1-Mediated Cardioprotection in a Large Animal Model of Chronic Coronary Artery Disease.

BACKGROUND: Coronary artery disease (CAD) imposes marked morbidity on patients, with many afflicted with debilitating residual symptoms despite optimal application of the available medical and surgical options. Glucagon-like peptide-1 (GLP-1) agonists have emerged from the resultant search for adjuncts as promising cardioprotective candidates in clinical trials. AIMS: We have previously characterized the augmented myocardial functional response to GLP-1 agonism; in this experiment, we aim to elucidate the molecular basis of this augmentation using highly sensitive proteomic analysis. METHODS: Yorkshire swine underwent surgical induction of CAD-associated ischemic cardiomyopathy through ameroid constrictor placement. Postoperatively, all were allocated either to receive semaglutide (n=6), or no drug (n=10) for 5 weeks, whereupon animals underwent myocardial resection and sectioning. The most ischemic ventricular sections were identified, from which tissue aliquots were fractionated using high-performance liquid chromatography and analyzed using mass spectrometry. RESULTS: There were 594 upregulated and 90 downregulated proteins identified in the semaglutide cohort compared with control cohort. Enrichment analysis revealed marked upregulation of multiple central metabolic pathways, including the glycolytic and tricarboxylic acid cycle pathways. The significantly downregulated proteomic fraction was found within pathways relevant to the induction of dilated and hypertrophic cardiomyopathy. CONCLUSIONS: Myocardial sections taken from semaglutide-treated animals exhibited a striking and multifaceted increase in metabolic flexibility. This result implicates enhanced resilience against the energetic strain imposed by ischemic disease as a mechanistic account of GLP-1-mediated cardioprotection.