GSK-3α overexpression attenuated Doxorubicin-induced mitochondrial dysfunction and apoptosis in human cardiomyocytes by activating the Keap1/Nrf2/HO-1 antioxidant pathway.
Does GSK-3α overexpression mitigate doxorubicin-induced apoptosis and oxidative stress in human cardiomyocytes?
GSK-3α activation mitigates doxorubicin-induced cardiomyocyte apoptosis and oxidative stress via the Keap1/Nrf2/HO-1 pathway, identifying it as a potential therapeutic target for Dox-induced cardiomyopathy.
AIMS Doxorubicin (Dox)-induced cardiomyopathy is marked by excessive oxidative stress, mitochondrial dysfunction and apoptosis, leading to progressive cardiac injury. Although glycogen synthase kinase-3 alpha (GSK-3α) regulates diverse cellular processes, its specific role in Dox-induced cardiomyocyte apoptosis and underlying signaling remains unknown. This study aimed to investigate whether GSK-3α regulates mitochondrial integrity, redox balance, and Nrf2 signaling under Dox stress. MATERIALS AND METHODS Human cardiomyocytes were subjected to Dox treatment with or without GSK-3α overexpression. Mitochondrial function, reactive oxygen species (ROS) generation, cytochrome-c (Cyt-c) release, autophagy markers, and Keap1/Nrf2/HO-1 signaling were assessed. Cytosolic and nuclear fractions were analysed to determine Nrf2 subcellular localization. KEY FINDINGS GSK-3α overexpression markedly attenuated Dox-induced mitochondrial dysfunction and apoptosis, as evidenced by reduced ROS generation, preserved mitochondrial membrane potential, and diminished Cyt-c release, a key initiator of caspase-dependent apoptosis. Mechanistically, GSK-3α reduced p62 and Keap1 expression while significantly increasing Nrf2 levels and its downstream effector HO-1 in Dox-treated cells. Importantly, fractionation studies revealed that GSK-3α specifically enhanced Dox-induced nuclear translocation of Nrf2, as evidenced by increased nuclear Nrf2 abundance and an elevated nuclear-to-cytosolic Nrf2 ratio. This enhanced nuclear accumulation supports transcriptional activation of antioxidant defences. Together with increased autophagic activity, these effects synergistically mitigated oxidative and apoptotic signaling. SIGNIFICANCE These findings identify GSK-3α as a novel regulator of the Keap1/Nrf2/HO-1 antioxidant pathway and demonstrate its anti-apoptotic roles in Dox-treated cardiomyocytes. GSK-3α thus emerges as a potential dual-action therapeutic target in Dox-induced cardiomyopathy.
Marzook et al. (Mon,) conducted a other in Doxorubicin-induced cardiomyopathy. GSK-3α overexpression vs. Doxorubicin treatment without GSK-3α overexpression was evaluated on Mitochondrial dysfunction, apoptosis, and Keap1/Nrf2/HO-1 signaling. GSK-3α overexpression attenuated Doxorubicin-induced mitochondrial dysfunction and apoptosis in human cardiomyocytes by activating the Keap1/Nrf2/HO-1 antioxidant pathway.