Proteomic Profiling of GLP-1-Mediated Cardioprotection in a Large Animal Model of Chronic Coronary Artery Disease
Main Article Content
Abstract
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.
Keywords:
Coronary Artery Disease, Large Animal Model, Translational Research, GLP-1 Agonist, Semaglutide, Cardiac Metabolism, Proteomics
Article Details
How to Cite
ZHENG, Clark et al.
Proteomic Profiling of GLP-1-Mediated Cardioprotection in a Large Animal Model of Chronic Coronary Artery Disease.
Medical Research Archives, [S.l.], v. 13, n. 11, dec. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7114>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i11.7114.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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22. Keeran KJ, Jeffries KR, Zetts AD, Taylor J, Kozlov S, Hunt TJ. A Chronic Cardiac Ischemia Model in Swine Using an Ameroid Constrictor. J Vis Exp JoVE. 2017;(128):56190. doi:10.3791/56190
23. Reinhardt CP, Dalhberg S, Tries MA, Marcel R, Leppo JA. Stable labeled microspheres to measure perfusion: validation of a neutron activation assay technique. Am J Physiol Heart Circ Physiol. 2001;280(1):H108-116. doi:10.1152/ajpheart.2001.280.1.H108
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25. Tabb DL, McDonald WH, Yates JR. DTASelect and Contrast: Tools for Assembling and Comparing Protein Identifications from Shotgun Proteomics. J Proteome Res. 2002;1(1):21-26.
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28. Kanehisa M, Goto S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 2000;28(1):27-30.
29. Luo W, Brouwer C. Pathview: an R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics. 2013;29(14):1830-1831. doi:10.1093/bioinformatics/btt285
30. Tamayo-Trujillo R, Ruiz-Pozo VA, Cadena-Ullauri S, et al. Molecular mechanisms of semaglutide and liraglutide as a therapeutic option for obesity. Front Nutr. 2024;11. doi:10.3389/fnut.2024.1398059
31. Solomon SD, Ostrominski JW, Wang X, et al. Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure. J Am Coll Cardiol. 2024;84(17):1587-1602. doi:10.1016/j.jacc.2024.08.021
32. Ouimet M, Hennessy EJ, van Solingen C, et al. miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux. Arterioscler Thromb Vasc Biol. 2016;36(5):942-951. doi:10.1161/ATVBAHA.116.307282
33. Haines RJ, Pendleton LC, Eichler DC. Argininosuccinate synthase: at the center of arginine metabolism. Int J Biochem Mol Biol. 2010;2(1):8-23.
34. Stone C, Harris D, Broadwin M, et al. Abstract 4113997: Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease. Circulation. 2024;150(Suppl_1):A4113997-A4113997. doi:10.1161/circ.150.suppl_1.4113997
35. Jacobi J, Sydow K, von Degenfeld G, et al. Overex-pression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis. Circulation. 2005;111(11): 1431-1438. doi:10.1161/01.CIR.0000158487.80483.09
36. Shen X, Zheng S, Metreveli NS, Epstein PN. Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes. 2006;55(3):798-805. doi:10.2337/diabetes.55.03.06.db05-1039
37. Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ. Mitochondrial dysfunction and oxidative stress in heart disease. Exp Mol Med. 2019;51(12):1-13. doi:10.1038/s12276-019-0355-7
38. Laurens C, Bourlier V, Mairal A, et al. Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle. Sci Rep. 2016;6(1):38310. doi:10.1038/srep38310
39. Okuda M, Inoue N, Azumi H, et al. Expression of Glutaredoxin in Human Coronary Arteries. Arterioscler Thromb Vasc Biol. 2001;21(9):1483-1487. doi:10.1161/hq0901.095550
40. Henriques BJ, Katrine Jentoft Olsen R, Gomes CM, Bross P. Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease. Gene. 2021;776:145407. doi:10.1016/j.gene.2021.145407
41. Chew A, Buck EA, Peretz S, Sirugo G, Rinaldo P, Isaya G. Cloning, expression, and chromosomal assignment of the human mitochondrial intermediate peptidase gene (MIPEP). Genomics. 1997;40(3):493-496. doi:10.1006/geno.1996.4586
42. Rowlands J, Heng J, Newsholme P, Carlessi R. Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function. Front Endocrinol. 2018;9. doi:10.3389/fendo.2018.00672
43. Gabr RE, El-Sharkawy AMM, Schär M, et al. Cardiac work is related to creatine kinase energy supply in human heart failure: a cardiovascular magnetic resonance spectroscopy study. J Cardiovasc Magn Reson. 2018;20(1):81. doi:10.1186/s12968-018-0491-6
44. Sinha S, Eisenhaber B, Jensen LJ, Kalbuaji B, Eisenhaber F. Darkness in the Human Gene and Protein Function Space: Widely Modest or Absent Illumination by the Life Science Literature and the Trend for Fewer Protein Function Discoveries Since 2000. PROTEOMICS. 2018;18(21-22):1800093. doi:10.1002/pmic.201800093
45. Science’s 2023 Breakthrough of the Year: Weight loss drugs with a real shot at fighting obesity. Accessed May 30, 2024. https://www.science.org/content/article/breakthrough-of-the-year-2023
46. Deanfield J, Verma S, Scirica BM, et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. The Lancet. 2024;404(10454): 773-786. doi:10.1016/S0140-6736(24)01498-3
47. Perreault L, Davies M, Frias JP, et al. Changes in Glucose Metabolism and Glycemic Status With Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants With Prediabetes in the STEP Program. Diabetes Care. 2022;45(10):2396-2405. doi:10.2337/dc21-1785
48. Baggio LL, Yusta B, Mulvihill EE, et al. GLP-1 Receptor Expression Within the Human Heart. Endocrinology. 2018;159(4):1570-1584. doi:10.1210/en.2018-00004
49. Czibik G, Steeples V, Yavari A, Ashrafian H. Citric Acid Cycle Intermediates in Cardioprotection. Circ Cardiovasc Genet. 2014;7(5):711-719. doi:10.1161/CIRCGENETICS.114.000220
50. Jiang M, Xie X, Cao F, Wang Y. Mitochondrial Metabolism in Myocardial Remodeling and Mechanical Unloading: Implications for Ischemic Heart Disease. Front Cardiovasc Med. 2021;8. doi:10.3389/fcvm.2021.789267
51. Liu M, Lv J, Pan Z, Wang D, Zhao L, Guo X. Mitochondrial dysfunction in heart failure and its therapeutic implications. Front Cardiovasc Med. 2022;9. doi:10.3389/fcvm.2022.945142
52. Lundberg E, Borner GHH. Spatial proteomics: a powerful discovery tool for cell biology. Nat Rev Mol Cell Biol. 2019;20(5):285-302. doi:10.1038/s41580-018-0094-y
2. Vaduganathan M, Mensah GA, Turco JV, Fuster V, Roth GA. The Global Burden of Cardiovascular Diseases and Risk. J Am Coll Cardiol. 2022;80(25):2361-2371. doi:10.1016/j.jacc.2022.11.005
3. Ralapanawa U, Sivakanesan R. Epidemiology and the Magnitude of Coronary Artery Disease and Acute Coronary Syndrome: A Narrative Review. J Epidemiol Glob Health. 2021;11(2):169-177. doi:10.2991/jegh.k.201217.001
4. Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association. doi:10.1161/CIR.0000000000001123
5. Dauerman HL. Reasonable Incomplete Revascularization. Circulation. 2011;123(21):2337-2340. doi:10.1161/CIRCULATIONAHA.111.033126
6. Stone GW, Kappetein AP, Sabik JF, et al. Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease. N Engl J Med. 2019;381(19):1820-1830. doi:10.1056/NEJMoa1909406
7. McGillion M, Arthur HM, Cook A, et al. Management of Patients With Refractory Angina: Canadian Cardiovascular Society/Canadian Pain Society Joint Guidelines. Can J Cardiol. 2012;28(2):S20-S41. doi:10.1016/j.cjca.2011.07.007
8. Sinha A, Rahman H, Perera D. Coronary microvascular disease: current concepts of pathophysiology, diagnosis and management. Cardiovasc Endocrinol Metab. 2020;10(1):22-30. doi:10.1097/XCE.0000000000000223
9. Terashvili M, Bosnjak ZJ. Stem Cell Therapies in Cardiovascular Disease. J Cardiothorac Vasc Anesth. 2019;33(1):209-222. doi:10.1053/j.jvca.2018.04.048
10. Deveza L, Choi J, Yang F. Therapeutic Angiogenesis for Treating Cardiovascular Diseases. Theranostics. 2012;2(8):801-814. doi:10.7150/thno.4419
11. Seyhan AA. Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles. Transl Med Commun. 2019;4(1):18. doi:10.1186/s41231-019-0050-7
12. Gilbert MP, Pratley RE. GLP-1 Analogs and DPP-4 Inhibitors in Type 2 Diabetes Therapy: Review of Head-to-Head Clinical Trials. Front Endocrinol. 2020;11:178. doi:10.3389/fendo.2020.00178
13. Lo CWH, Fei Y, Cheung BMY. Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes. Card Fail Rev. 2021;7:e04. doi:10.15420/cfr.2020.19
14. GLP1RAs in Clinical Practice: Therapeutic Advances and Safety Perspectives. American College of Cardiology. Accessed November 29, 2024. https://www.acc.org/Latest-in-Cardiology/Articles/2024/04/15/11/19/http%3a%2f%2fwww.acc.org%2fLatest-in-Cardiology%2fArticles%2f2024%2f04%2f15%2f11%2f19%2fGLP1RAs-in-Clinical-Practice
15. Ussher JR, Drucker DJ. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat Rev Cardiol. 2023;20(7): 463-474. doi:10.1038/s41569-023-00849-3
16. Lincoff A. Michael, Brown-Frandsen Kirstine, Colhoun Helen M., et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563
17. Stone CR, Harris DD, Broadwin M, et al. Crafting a Rigorous, Clinically Relevant Large Animal Model of Chronic Myocardial Ischemia: What Have We Learned in 20 Years? Methods Protoc. 2024;7(1):17. doi:10.3390/mps7010017
18. Stone C, Harris DD, Broadwin M, et al. Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease. Arterioscler Thromb Vasc Biol. 2025;45(2):285-297. doi:10.1161/ATVBAHA.124.321850
19. O’Konski MS, White FC, Longhurst J, Roth D, Bloor CM. Ameroid constriction of the proximal left circumflex coronary artery in swine. A model of limited coronary collateral circulation. Am J Cardiovasc Pathol. 1987;1(1):69-77.
20. Herrmann JL. Do Ameroid Constrictors Reliably Occlude Porcine Coronary Arteries? J Surg Res. 2010;161(1):36-37. doi:10.1016/j.jss.2009.05.047
21. Husain Mansoor, Birkenfeld Andreas L., Donsmark Morten, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841-851. doi:10.1056/NEJMoa1901118
22. Keeran KJ, Jeffries KR, Zetts AD, Taylor J, Kozlov S, Hunt TJ. A Chronic Cardiac Ischemia Model in Swine Using an Ameroid Constrictor. J Vis Exp JoVE. 2017;(128):56190. doi:10.3791/56190
23. Reinhardt CP, Dalhberg S, Tries MA, Marcel R, Leppo JA. Stable labeled microspheres to measure perfusion: validation of a neutron activation assay technique. Am J Physiol Heart Circ Physiol. 2001;280(1):H108-116. doi:10.1152/ajpheart.2001.280.1.H108
24. Vitko D, Chou WF, Nouri Golmaei S, et al. timsTOF HT Improves Protein Identification and Quantitative Reproducibility for Deep Unbiased Plasma Protein Biomarker Discovery. J Proteome Res. 2024;23(3):929-938. doi:10.1021/acs.jproteome.3c00646
25. Tabb DL, McDonald WH, Yates JR. DTASelect and Contrast: Tools for Assembling and Comparing Protein Identifications from Shotgun Proteomics. J Proteome Res. 2002;1(1):21-26.
26. Yue L, Chen S, Ren Q, et al. Effects of semaglutide on vascular structure and proteomics in high-fat diet-induced obese mice. Front Endocrinol. 2022;13: 995007. doi:10.3389/fendo.2022.995007
27. Ge SX, Jung D, Yao R. ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics. 2020;36(8):2628-2629. doi:10.1093/bioinformatics/btz931
28. Kanehisa M, Goto S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 2000;28(1):27-30.
29. Luo W, Brouwer C. Pathview: an R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics. 2013;29(14):1830-1831. doi:10.1093/bioinformatics/btt285
30. Tamayo-Trujillo R, Ruiz-Pozo VA, Cadena-Ullauri S, et al. Molecular mechanisms of semaglutide and liraglutide as a therapeutic option for obesity. Front Nutr. 2024;11. doi:10.3389/fnut.2024.1398059
31. Solomon SD, Ostrominski JW, Wang X, et al. Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure. J Am Coll Cardiol. 2024;84(17):1587-1602. doi:10.1016/j.jacc.2024.08.021
32. Ouimet M, Hennessy EJ, van Solingen C, et al. miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux. Arterioscler Thromb Vasc Biol. 2016;36(5):942-951. doi:10.1161/ATVBAHA.116.307282
33. Haines RJ, Pendleton LC, Eichler DC. Argininosuccinate synthase: at the center of arginine metabolism. Int J Biochem Mol Biol. 2010;2(1):8-23.
34. Stone C, Harris D, Broadwin M, et al. Abstract 4113997: Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease. Circulation. 2024;150(Suppl_1):A4113997-A4113997. doi:10.1161/circ.150.suppl_1.4113997
35. Jacobi J, Sydow K, von Degenfeld G, et al. Overex-pression of Dimethylarginine Dimethylaminohydrolase Reduces Tissue Asymmetric Dimethylarginine Levels and Enhances Angiogenesis. Circulation. 2005;111(11): 1431-1438. doi:10.1161/01.CIR.0000158487.80483.09
36. Shen X, Zheng S, Metreveli NS, Epstein PN. Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes. 2006;55(3):798-805. doi:10.2337/diabetes.55.03.06.db05-1039
37. Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ. Mitochondrial dysfunction and oxidative stress in heart disease. Exp Mol Med. 2019;51(12):1-13. doi:10.1038/s12276-019-0355-7
38. Laurens C, Bourlier V, Mairal A, et al. Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle. Sci Rep. 2016;6(1):38310. doi:10.1038/srep38310
39. Okuda M, Inoue N, Azumi H, et al. Expression of Glutaredoxin in Human Coronary Arteries. Arterioscler Thromb Vasc Biol. 2001;21(9):1483-1487. doi:10.1161/hq0901.095550
40. Henriques BJ, Katrine Jentoft Olsen R, Gomes CM, Bross P. Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease. Gene. 2021;776:145407. doi:10.1016/j.gene.2021.145407
41. Chew A, Buck EA, Peretz S, Sirugo G, Rinaldo P, Isaya G. Cloning, expression, and chromosomal assignment of the human mitochondrial intermediate peptidase gene (MIPEP). Genomics. 1997;40(3):493-496. doi:10.1006/geno.1996.4586
42. Rowlands J, Heng J, Newsholme P, Carlessi R. Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function. Front Endocrinol. 2018;9. doi:10.3389/fendo.2018.00672
43. Gabr RE, El-Sharkawy AMM, Schär M, et al. Cardiac work is related to creatine kinase energy supply in human heart failure: a cardiovascular magnetic resonance spectroscopy study. J Cardiovasc Magn Reson. 2018;20(1):81. doi:10.1186/s12968-018-0491-6
44. Sinha S, Eisenhaber B, Jensen LJ, Kalbuaji B, Eisenhaber F. Darkness in the Human Gene and Protein Function Space: Widely Modest or Absent Illumination by the Life Science Literature and the Trend for Fewer Protein Function Discoveries Since 2000. PROTEOMICS. 2018;18(21-22):1800093. doi:10.1002/pmic.201800093
45. Science’s 2023 Breakthrough of the Year: Weight loss drugs with a real shot at fighting obesity. Accessed May 30, 2024. https://www.science.org/content/article/breakthrough-of-the-year-2023
46. Deanfield J, Verma S, Scirica BM, et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. The Lancet. 2024;404(10454): 773-786. doi:10.1016/S0140-6736(24)01498-3
47. Perreault L, Davies M, Frias JP, et al. Changes in Glucose Metabolism and Glycemic Status With Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants With Prediabetes in the STEP Program. Diabetes Care. 2022;45(10):2396-2405. doi:10.2337/dc21-1785
48. Baggio LL, Yusta B, Mulvihill EE, et al. GLP-1 Receptor Expression Within the Human Heart. Endocrinology. 2018;159(4):1570-1584. doi:10.1210/en.2018-00004
49. Czibik G, Steeples V, Yavari A, Ashrafian H. Citric Acid Cycle Intermediates in Cardioprotection. Circ Cardiovasc Genet. 2014;7(5):711-719. doi:10.1161/CIRCGENETICS.114.000220
50. Jiang M, Xie X, Cao F, Wang Y. Mitochondrial Metabolism in Myocardial Remodeling and Mechanical Unloading: Implications for Ischemic Heart Disease. Front Cardiovasc Med. 2021;8. doi:10.3389/fcvm.2021.789267
51. Liu M, Lv J, Pan Z, Wang D, Zhao L, Guo X. Mitochondrial dysfunction in heart failure and its therapeutic implications. Front Cardiovasc Med. 2022;9. doi:10.3389/fcvm.2022.945142
52. Lundberg E, Borner GHH. Spatial proteomics: a powerful discovery tool for cell biology. Nat Rev Mol Cell Biol. 2019;20(5):285-302. doi:10.1038/s41580-018-0094-y