Akademik Veri Yönetim Sistemi
h European Section Meeting of the International Academy of Cardiovascular Sciences, Szeged, Macaristan, 28 Eylül - 01 Ekim 2022
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 cardioprotective action in aging-heart.
Therefore, we examined the effects of GLP-1R agonist liraglutide treatment (4
weeks) on systemic parameters of aged rats (24-mo-old) compared to those of
adult rats (6-mo-old) such as electrocardiograms (ECGs) and blood pressures. At
cellular levels, action potential (AP) parameters, ionic currents, and Ca2+-regulation
were examined in freshly isolated ventricular cardiomyocytes. The liraglutide
treatment of aged rats significantly reserved the prolongations in ECG
parameters and increases in both systolic and diastolic pressures together with
recoveries in plasma oxidant and antioxidant status. The prolonged AP durations
and depolarized membrane potentials of the isolated cardiomyocytes from the
aged rats were found to be normalized via recoveries in K+-channel
currents with liraglutide treatment. The alterations in Ca2+-regulation
including leaky-ryanodine receptors could be also reserved via recoveries in Na+/Ca2+-exchanger
currents with this treatment. Direct treatment of isolated aged-rat
cardiomyocytes with liraglutide could recover the depolarized mitochondrial
membrane potential, the increase in both reactive oxygen and nitrogen species
(ROS and RNS), and cytosolic Na+-level, although Na+-channel
currents were not affected by aging. Interestingly, the liraglutide treatment of aged-rat
cardiomyocytes provided significant inhibition of activated 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 (eNOS)
level to eNOS protein level in the treated ventricular cardiomyocytes implies
the involvement of liraglutide-associated inhibition of oxidative
stress-induced injury via IRS1-eNOS-PKG pathway in aging-heart. Interestingly, marked
irregular atypical fibrillations and significant prolongation of the QT
intervals in in situ ECGs were observed following an acute GLP agonist
application. Unlikely to adult group, GLP agonism prolonged APs, reduce
K-currents and increased the Ca+2-spark frequency in the aged
cardiomyocytes, while Na-channels become resurgent after GLP activation
implying higher propensity for arrhythmias. Overall,
our data, for the first time, provide important information on the direct
cardioprotective effects of GLP-1R agonism in the hearts of aged rats in a
differential manner as chronic or acute effects.