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Proteomic Profiling of GLP-1-Mediated Cardioprotection in a Large Animal Model of Chronic Coronary Artery Disease
Clark Zheng1, Christopher Stone1, Kelsey Muir1
1Division of Cardiothoracic Surgery, Department of Surgery, The Warren Alpert Medical School of Brown University.
Insights
Glucagon-like peptide-1 (GLP-1) agonists like semaglutide enhance heart metabolism in coronary artery disease models. This proteomic study reveals increased metabolic flexibility, suggesting a mechanism for GLP-1
Area of Science:
- Cardiology
- Metabolomics
- Molecular Biology
Background:
- Coronary artery disease (CAD) causes significant patient morbidity, often with persistent symptoms despite treatment.
- Glucagon-like peptide-1 (GLP-1) agonists show promise as cardioprotective agents in clinical trials for CAD.
- Previous work demonstrated enhanced myocardial function with GLP-1 agonism.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the cardioprotective effects of GLP-1 agonism.
- To utilize high-sensitivity proteomic analysis to understand GLP-1's impact on myocardial function.
- To identify specific protein expression changes induced by semaglutide in a CAD model.
Main Methods:
- Yorkshire swine underwent surgical induction of ischemic cardiomyopathy via ameroid constrictor.
- Animals received either semaglutide or no drug for five weeks.
- Proteomic analysis (mass spectrometry) was performed on myocardial tissue from ischemic regions.
Main Results:
- Semaglutide treatment led to 594 upregulated and 90 downregulated proteins compared to controls.
- Enrichment analysis showed increased activity in central metabolic pathways (glycolysis, TCA cycle).
- Downregulated proteins were associated with pathways linked to dilated and hypertrophic cardiomyopathy.
Conclusions:
- Semaglutide significantly increased metabolic flexibility in the myocardium.
- Enhanced metabolic resilience against ischemic stress is a key mechanism of GLP-1-mediated cardioprotection.
- These findings support GLP-1 agonists as a therapeutic strategy for heart 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.
