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

Abstract

ABSTRACT

Background: Cardiac remodeling (CR) refers to the molecular, interstitial, and cellular alterations in the shape, size, mass, and function of the heart following an injury that may be physiological or pathological such as due to increased workload after exercise or myocardial infarction (MI), aortic stenosis, myocarditis, hypertension, or valvular regurgitation. Initially an adaptive response to preserve cardiac function, CR can become maladaptive through reduced SERCA2a activity, and increased oxidative stress, fibrosis, inflammation, and apoptosis eventually leading to cardiac dysfunction. Semaglutide is a GLP-1 receptor agonist mainly used in managing type-2 diabetes and aiding in weight loss. It has also shown potential in reducing cardiac hypertrophy and improving cardiac health which will be explored in this review.

Aims: To explore the effects of semaglutide on cardiac remodeling, mainly its impact on cardiac hypertrophy, inflammation, fibrosis, oxidative stress, and apoptosis in mice models.

Methods: The literature search was conducted by making use of databases such as PubMed, Google Scholar, Springer Link, Cochrane, Nature, JACC, and Science Direct deploying keywords that included ‘semaglutide’, ‘cardiac remodeling’, ‘heart failure’, ‘HFpEF’, and ‘cardiac hypertrophy’. Studies on male and female mice discussing the effects of semaglutide on hypertrophy, oxidative stress, inflammatory markers, and cardiac remodeling were included. Those lacking a proper control group, with subjects other than mice and focusing effects of semaglutide for other conditions were excluded. Data were extracted using the PICO framework.

Results: Semaglutide consistently reduced body weight, fat mass, tissue-specific inflammation, apoptosis, and oxidative stress in mice. It substantially mitigates cardiac hypertrophy by reducing heart weight, and left ventricular mass, and improved cellular architecture leading to better cardiac output. Inflammatory markers critical in the pathogenesis of CR such as TNF-α, IL-6, atrial natriuretic peptide along with others are also markedly reduced on treatment with semaglutide. It also significantly attenuates fibrosis on both molecular and histologic levels by decreasing collagen deposition and reducing markers of fibrosis such as collage 1a1 and collagen 3a1. Moreover, it reduces oxidative stress by lowering levels of NOX2 and malondialdehyde, key indicators of oxidative burst. Upregulation of antioxidant pathways along with a rise in antioxidant enzymes such as superoxide dismutase (SOD) and catalase is seen. Furthermore, administration of semaglutide also mitigates apoptosis by significantly reducing BAX and slightly decreasing caspase-3, two of the important apoptosis-related proteins.

Conclusion: Results demonstrate the significant potential of semaglutide for managing cardiac remodeling (CR), particularly in obese patients. It showed considerable cardioprotective effects through the regulation of hypertrophy, oxidative stress, inflammation, apoptosis, fibrosis, and lipid metabolism. These benefits are suggestive of its viability as a promising therapeutic agent for cardiac disorders. However, more clinical trials especially on humans might be required to validate these findings and determine the right dosing.