Enhanced cardioprotective effects of resveratrol and liraglutide against isoproterenol-induced myocardial injury: role of oxidative stress, inflammation, and mitochondrial function

Abstract Background: Myocardial infarction (MI) remains a leading cause of global mortality and is strongly associated with oxidative stress, mitochondrial dysfunction, and inflammatory responses that contribute to irreversible cardiac injury. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide, have demonstrated cardioprotective effects beyond glycemic control, while resveratrol, a natural polyphenol, exhibits potent antioxidant and mitochondrial-protective properties. However, the combined effects of these agents on mitochondrial function in myocardial injury have not been fully explored. Objective: This study aimed to evaluate the combined cardioprotective effects of resveratrol and a GLP-1 receptor agonist (liraglutide) against isoproterenol (ISO)-induced myocardial injury in rats, with particular emphasis on oxidative stress and mitochondrial dysfunction. Methods: Seventy adult male albino rats were randomly allocated into five groups: Control, ISO (100 mg/kg, s.c., for two consecutive days), Resveratrol + ISO (20 mg/kg/day, orally for 28 days), GLP-1 RA + ISO (liraglutide 0.2 mg/kg/day, s.c., for 10 days), and Resveratrol + GLP-1 RA + ISO. ISO was administered on days 27 and 28. Cardiac injury was assessed using serum biomarkers (cTnI, CK-MB, LDH), oxidative stress markers (MDA, SOD, GSH), inflammatory cytokines (TNF-α, IL-6), and mitochondrial function parameters, including mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) generation. Histopathological evaluation of cardiac tissue was also performed. Results: ISO administration significantly increased cardiac injury markers, lipid peroxidation, and pro-inflammatory cytokines, while reducing antioxidant defenses and impairing mitochondrial function (p < 0.001 vs. control). Pretreatment with either resveratrol or liraglutide partially attenuated these changes. The combined treatment resulted in significantly greater improvement compared to either monotherapy (p < 0.01), including reductions in MDA (~ 45%) and inflammatory cytokines, along with restoration of antioxidant capacity and mitochondrial function. Two-way ANOVA revealed significant interaction effects between treatments (p < 0.05). Histopathological findings supported the biochemical results, showing marked preservation of myocardial architecture in the combination group. Conclusion: The combined administration of resveratrol and liraglutide provides enhanced cardioprotection against ISO-induced myocardial injury, likely through complementary effects on oxidative stress, inflammation, and mitochondrial function. While interaction analysis suggests a greater-than-additive effect, further studies using dedicated synergy models and molecular validation are required. This combination may represent a promising therapeutic strategy for myocardial injury.