Review Article

Efficacy of Semaglutide in Modulating Cardiac Remodeling in Mice: A Review of Mechanisms and Outcomes

Abstract

Objective: This review evaluates the efficacy of semaglutide in reducing cardiac hypertrophy and enhancing cardiac function in mouse studies.
Methods: A literature search was conducted using databases such as PubMed, Google Scholar, SpringerLink, Cochrane, Nature, JACC, and ScienceDirect. Keywords included “semaglutide,” “cardiac remodeling,” “heart failure,” “heart failure with preserved ejection fraction (HFpEF),” and “cardiac hypertrophy.” Studies involving male and female mice that discussed the effects of semaglutide on hypertrophy, oxidative stress, inflammatory markers, and cardiac remodeling were included. Data were extracted using the PICO framework.
Results: Semaglutide consistently led to reductions in body weight, fat mass, tissue-specific inflammation, apoptosis, and oxidative stress in mice. It significantly alleviated cardiac hypertrophy, as evidenced by decreased heart weight and left ventricular mass, and improved cardiac output through enhanced cellular architecture. Inflammatory markers such as tumor necrosis factor α, interleukin 6, and atrial natriuretic peptide were notably reduced. Fibrosis was significantly attenuated at both molecular and histological levels, with decreased collagen deposition and lower markers such as collagen 1a1 and collagen 3a1. Oxidative stress markers NADPH oxidase 2 and malondialdehyde were reduced, accompanied by increased antioxidant enzymes, including superoxide dismutase and catalase. Additionally, semaglutide reduced apoptosis, evidenced by lower levels of Bcl-2-associated X protein (BAX) and slightly decreased caspase-3.
Conclusion: The results demonstrate the significant potential of semaglutide for managing cardiac remodeling. Semaglutide showed considerable cardioprotective effects through the regulation of hypertrophy, oxidative stress, inflammation, apoptosis, fibrosis, and lipid metabolism. These benefits suggest its viability as a promising therapeutic agent for cardiac disorders. Nonetheless, more clinical trials, particularly in humans, are required to validate these findings and determine appropriate dosing.

1. Azevedo PS, Polegato BF, Minicucci MF, Paiva SAR, Zornoff LAM. Cardiac Remodeling: Concepts, Clinical Impact, Pathophysiological Mechanisms and Pharmacologic Treatment. Arq Bras Cardiol. 2016 Jan;106(1):62-9.
2. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol. 2000 Mar 1;35(3):569-82.
3. Mehrpooya M, Vaseghi G, Eshraghi A, Eslami N. Delayed myocardial infarction associated with rituximab infusion. Am J Ther. 2015 Jul 21;23(1):e283-7.
4. Tham YK, Bernardo BC, Ooi JYY, Weeks KL, McMullen JR. Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol. 2015 Sep;89(9):1401-38.
5. Cutler MJ, Jeyaraj D, Rosenbaum DS. Cardiac electrical remodeling in health and disease. Trends Pharmacol Sci. 2011 Mar;32(3):174-80.
6. Eshraghi A, Talasaz AH, Salamzadeh J, Salarifar M, Pourhosseini H, Nozari Y, et al. Evaluating the effect of intracoronary N-Acetylcysteine on platelet activation markers after primary percutaneous coronary intervention in patients with ST-Elevation myocardial infarction. Am J Ther. 2015 Aug 20;23(1):e44-51.
7. Wang Q, Yu X, Dou L, Huang X, Zhu K, Guo J, et al. miR-154-5p Functions as an Important Regulator of Angiotensin II-Mediated Heart Remodeling. Oxid Med Cell Longev. 2019 Sep 12;2019:8768164.
8. Rosano GM, Vitale C. Metabolic Modulation of Cardiac Metabolism in Heart Failure. Card Fail Rev. 2018 Aug;4(2):99-103.
9. Gjesdal O, Bluemke DA, Lima JA. Cardiac remodeling at the population level—risk factors, screening, and outcomes. Nat Rev Cardiol. 2011 Oct 25;8(12):673-85.
10. Drugs.com. Semaglutide: uses, dosage, side effects, brands.
11. Rehman A, Saidullah S, Asad M, Gondal UR, Ashraf A, Khan MF, et al. Efficacy and safety of semaglutide in patients with heart failure with preserved ejection fraction and obesity. Clin Cardiol. 2024 May;47(5):e24283.
12. Yan M, Lin K, Huang D, Li J, Qu X, Chen K. Semaglutide attenuates pathological electrophysiological remodeling in diabetic cardiomyopathy via restoring Cx43 expression. Endocrine. 2024 Jun;84(3):969-79.
13. He W, Wei J, Liu X, Zhang Z, Huang R, Jiang Z. Semaglutide ameliorates pressure overload-induced cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome. Sci Rep. 2024 May 23;14(1):11824.
14. Li X, Luo W, Tang Y, Wu J, Zhang J, Chen S, et al. Semaglutide attenuates doxorubicin induced cardiotoxicity by ameliorating BNIP3-Mediated mitochondrial dysfunction. Redox Biol. 2024 Jun;72:103129.
15. Li Q, Tuo X, Li B, Deng Z, Qiu Y, Xie H. Semaglutide attenuates excessive exercise induced myocardial injury through inhibiting oxidative stress and inflammation in rats. Life Sciences. 2020 Jun 1;250:117531.
16. Pan X, Yue L, Ban J, Ren L, Chen S. Effects of Semaglutide on Cardiac Protein Expression and Cardiac Function of Obese Mice. JIR. 2022 Nov 24;15:6409-25.
17. Ma YL, Kong CY, Guo Z, Wang MY, Wang P, Liu FY, et al. Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis. Nat Commun. 2024 Jun 4;15(1):4757.
18. Withaar C, Meems LMG, Nollet EE, Schouten EM, Schroeder MA, Knudsen LB, et al. The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice with HFpEF. JACC Basic Transl Sci. 2023 Oct 1;8(10):1298-314.
19. Borghetti G, von Lewinski D, Eaton DM, Sourij H, Houser SR, Wallner M. Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control. Front Physiol. 2018;9:1514.
20. Nah J, Shirakabe A, Mukai R, Zhai P, Sung EA, Ivessa A, et al. Ulk1-dependent alternative mitophagy plays a protective role during pressure overload in the heart. Cardiovasc Res. 2022. 20;118(12):2638-51.
21. Tang X, Pan L, Zhao S, Dai F, Chao M, Jiang H, et al. SNO-MLP (S-Nitrosylation of Muscle LIM Protein) Facilitates Myocardial Hypertrophy Through TLR3 (Toll-Like Receptor 3)-Mediated RIP3 (Receptor-Interacting Protein Kinase 3) and NLRP3 (NOD Like Receptor Pyrin Domain Containing 3) Inflammasome Activation. Circulation. 2020 Mar 24;141(12):984-1000.
22. Global BMI Mortality Collaboration, Di Angelantonio E, Bhupathiraju S, Wormser D, Gao P, Kaptoge S, et al. Body-mass index and all-cause mortality: individual participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016 Aug 20;388(10046):776-86.
23. O’Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018 Aug 25;392(10148):637-49.
24. Piché ME, Tchernof A, Després JP. Obesity Phenotypes, Diabetes, and Cardiovascular Diseases. Circ Res. 2020 May 22;126(11):1477-500.
25. Powell-Wiley TM, Poirier CP, Burke VCLE, Després JP, Gordon-Larsen P, Lavie CJ, et al. Obesity and Cardiovascular Disease. Circulation. 2021 May 25;143(21):e984-1010.
26. De Geest B, Mishra M. Role of Oxidative Stress in Diabetic Cardiomyopathy. Antioxidants. 2022 Apr 15;11(4):784.
27. Wang J, Wang S, Wang J, Xiao M, Guo Y, Tang Y, et al. Epigenetic Regulation Associated With Sirtuin 1 in Complications of Diabetes Mellitus. Front Endocrinol (Lausanne). 2021 Jan 18;11:598012.
28. Rindler PM, Plafker SM, Szweda LI, Kinter M. High dietary fat selectively increases catalase expression within cardiac mitochondria. J Biol Chem. 2013 Jan 18;288(3):1979-90.
29. Packer M. Role of Deranged Energy Deprivation Signaling in the Pathogenesis of Cardiac and Renal Disease in States of Perceived Nutrient Overabundance. Circulation. 2020 Jun 23;141(25):2095-105.
30. Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, et al. NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell. 2016 Feb 25;164(5):896-910.
31. Zhang H, Xiong Z, Wang J, Zhang S, Lei L, Yang L, et al. Glucagon-like peptide-1 protects cardiomyocytes from advanced oxidation protein product-induced apoptosis via the PI3K/Akt/Bad signaling pathway. Mol Med Rep. 2016 Feb;13(2):1593-601.
Files
IssueVol 20 No 3 (2025) QRcode
SectionReview Article(s)
DOI https://doi.org/10.18502/jthc.v20i3.20114
Keywords
Cardiac Remodeling Cardiac Hypertrophy Cardioprotection Heart Failure Oxidative Stress Inflammation Apoptosis Semaglutide Glucagon-Like Peptide
Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Fairy R, Ali L, Azam H, Khurram A, Shahzaib M, Tariq H, Rashmeen S, Hassan H. Efficacy of Semaglutide in Modulating Cardiac Remodeling in Mice: A Review of Mechanisms and Outcomes. Res Heart Yield Transl Med. 2025;20(3):221-230.