Liraglutide provides cardioprotection through the recovery of mitochondrial dysfunction and oxidative stress in aging hearts

Glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular dysfunction via the pleiotropic effects behind their receptor action. However, it is unknown whether they have a cardioprotective action in the hearts of the elderly. Therefore, we examined the effects of GLP-1R agonist liraglutide treatment (LG, 4 weeks) on the systemic parameters of aged rats (24-month-old) compared to those of adult rats (6-month-old) such as electrocardiograms (ECGs) and systolic and diastolic blood pressure (SBP and DBP). At the cellular level, the action potential (AP) parameters, ionic currents, and Ca²⁺ regulation were examined in freshly isolated ventricular cardiomyocytes. The LG treatment of aged rats significantly ameliorated the prolongation of QRS duration and increased both SBP and DBP together with recovery in plasma oxidant and antioxidant statuses. The prolonged AP durations and depolarized membrane potentials of the isolated cardiomyocytes from the aged rats were normalized via recoveries in K⁺ channel currents with LG treatment. The alterations in Ca²⁺ regulation including leaky-ryanodine receptors (RyR2) could be also ameliorated via recoveries in Na⁺/Ca²⁺ exchanger currents with this treatment. A direct LG treatment of isolated aged rat cardiomyocytes could recover the depolarized mitochondrial membrane potential, the increase in both reactive oxygen and nitrogen species (ROS and RNS), and the cytosolic Na⁺ level, although the Na⁺ channel currents were not affected by aging. Interestingly, LG treatment of aged rat cardiomyocytes provided a significant inhibition of activated sodium-glucose co-transporter-2 (SGLT2) and recoveries in the depressed insulin receptor substrate 1 (IRS1) and increased protein kinase G (PKG). The recovery in the ratio of phospho-endothelial nitric oxide (pNOS3) level to NOS3 protein level in LG-treated cardiomyocytes implies the involvement of LG-associated inhibition of oxidative stress-induced injury via IRS1-eNOS-PKG pathway in the aging heart. Overall, our data, for the first time, provide important information on the direct cardioprotective effects of GLP-1R agonism with LG in the hearts of aged rats through an examination of recoveries in mitochondrial dysfunction, and both levels of ROS and RNS in left ventricular cardiomyocytes.