Effects of GLP-1 Receptor Agonism on Isoproterenol-Induced Cardiomyopathy: Roles of Cardiac Oxidative Stress and the SIRT1/PGC-1α Pathway

Background: A single high dose of isoproterenol (ISO) induces acute cardiac dysfunction with features resembling catecholamine-induced cardiomyopathy and selected aspects of Takotsubo syndrome (TTS), accompanied by heightened oxidative stress. Although glucagon-like peptide-1 (GLP-1) receptor agonists exert established cardioprotective effects, their role in catecholamine-mediated myocardial injury remains incompletely understood. The present study investigated whether liraglutide (LIR) alleviates ISO-induced TTS-like cardiomyopathy in ovariectomized (OVX) rats and explored the potential underlying molecular pathways. Methods: Surgical menopause was induced in adult female Wistar Albino rats via bilateral ovariectomy six weeks prior to experimentation. Rats were randomized into three groups (n = 8 per group): OVX control, ISO-induced TTS-like cardiomyopathy (single intraperitoneal injection of 150 mg/kg ISO), and ISO plus LIR treatment (150 µg/kg/day subcutaneously for five days before and two days after ISO administration). Cardiac function was evaluated by transthoracic echocardiography at 90 minutes, 24 hours, and 48 hours following ISO administration. Myocardial oxidative and nitrosative stress markers—malondialdehyde (MDA), reduced glutathione (GSH), and nitrate—as well as myocardial sirtuin-1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein levels were quantified. Results: ISO administration induced severe left ventricular systolic dysfunction and ST-segment elevation, accompanied by markedly reduced myocardial SIRT1 and PGC-1α protein expression. In LIR-treated rats, ISO-induced left ventricular systolic dysfunction was significantly attenuated at 48 hours, and myocardial MDA and nitrate levels were significantly reduced compared with the untreated ISO group. Furthermore, LIR treatment significantly restored myocardial SIRT1 and PGC-1α protein expression compared with ISO administration alone. Conclusion: Pretreatment with LIR is associated with improved left ventricular systolic function in an OVX rat model of ISO-induced TTS-like cardiomyopathy, potentially mediated through the attenuation of myocardial oxidative and nitrosative stress and the preservation of SIRT1/PGC-1α signaling.