Microvascular endothelial cells (CMECs) oxidative damage resulting from
hypoxia/reoxygenation (H/R) injury is responsible for microcirculation perfusion disturbances and the progression of cardiac dysfunction. However, few strategies are available to reverse such pathologies. Here, we studied the effects and mechanisms of
liraglutide on CEMCs oxidative damage, focusing in particular on
calcium overload-triggered
free radical injury signals and the GLP-1R/PI3K/Akt/
survivin survival pathways. The results indicate that H/R increased IP3R expression but reduced SERCA2a expression, which rapidly raised intracellular Ca(2+) levels, subsequently leading to Ca(2+)-dependent
xanthine oxidase (XO) activation,
reactive oxygen species (ROS) production and the cellular apoptosis of CMECs. However,
liraglutide pretreatment abrogated Ca(2+)-mediated oxidative apoptosis. Furthermore,
liraglutide regulated the rate of IP3R/SERCA2a gene transcription and conserved SERCA2a-ATPase activity via the maintenance of
ATP production under H/R, which drove excessive Ca(2+) reflux to the sarcoplasmic reticulum (SR) and inhibited Ca(2+) release from the SR, ultimately restoring Ca(2+) homeostasis. Furthermore, the regulatory role of
liraglutide on Ca(2+) balance in conjunction with its up-regulation of
superoxide dismutase,
glutathione and
glutathione peroxidase collectively scavenged the excess ROS under H/R. Moreover, we showed that
liraglutide strengthened Akt phosphorylation and subsequently
survivin expression. In addition, both the blockade of the GLP-1R/PI3K/Akt pathways and the
siRNA-mediated knockdown of
survivin abolished the protective effects of
liraglutide on SR-Ca(2+) function and CMECs oxidative apoptosis. In summary, this study confirmed that H/R induced CMECs oxidative damage through the SR-Ca(2+)-XO-ROS injury signals and that
liraglutide pretreatment may suppress such CMECs damage through the PI3K/Akt/
survivin pathways.