Original Research

Glycogen Synthase Kinase 3β Inhibition Protects the Cardiomyocytes from Anoxia/Reoxygenation Injury by Modulating Inflammatory Response and Reducing the Opening of mPTP

Yi Cheng , Jun Ma , Fu-Shan Xue , Xin-Long Cui
Center for Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China, Department of Anesthesiology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
J Anesth Perioper Med 2015; 2(5): 244- 250 . Published on Aug 6, 2015 . doi:10.24015/JAPM.2015.0033
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Abstract

Background: Phosphorylation of glycogen synthase kinase 3β (GSK-3β) is crucial in multiple cardioprotective signaling pathways. But the downstream mechanism is unclear. Considering GSK-3β is the key regulator of nuclear factor-κB (NF-κB) and mitochondrial permeability transition pore (mPTP) is a critical determinant of lethal reperfusion injury, we assessed the mechanism of postconditioning with the selective inhibitor of GSK-3β associated with modulating inflammatory response and reducing the opening of mPTP.

Methods: After cultured for 72 hours, neonatal rat cardiomyocytes were randomly divided into 3 groups according to random number table: Sham group, anoxia/reoxygenation injury group (AR group) and GSK-3β inhibitor TDZD-8 postconditioning group (TDZD-8 group). At the end of the experiment, the lactate dehydrogenase (LDH) release rate, myocardial apoptosis and the supernatant concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured. The NF-κBp65 and phosphorylated NF-κBp65Ser536 in all samples were assessed by western-blotting technique. The mitochondrial membrane potential was measured by rhodamine 123 staining flow cytometry and confocal laser scanning microscope. 

Results: We discovered that postconditioning with GSK-3β inhibitor TDZD-8 could significantly protect against cardiomyocyte anoxia/reoxygenation injury, as shown by reducing the early apoptosis and LDH release rate. And this cardioprotective method could significantly attenuate inflammatory response to the anoxia/reoxygenation injury, as evidenced by decreasing the activity of NF-κB and levels of inflammatory cytokines, such as IL-6 and TNF-α. Furthermore, it could significantly reduce the irreversibly high level opening of the mPTP, as evidenced by increasing the mitochondrial membrane potential of anoxia/reoxygenation cardiomyocyte.

Conclusions: Our current results indicated that postconditioning with GSK-3β inhibitor TDZD-8 significantly attenuated the systemic inflammatory and reduced the opening of mPTP response to cardiomyocytes anoxia/reoxygenation injury.

 

 

Citation:  Yi Cheng, Jun Ma, Fu-Shan Xue, Xin-Long Cui. Glycogen synthase kinase 3β inhibition protects the cardiomyocytes from anoxia/reoxygenation injury by modulating inflammatory response and reducing the opening of mPTP. J Anesth Perioper Med 2015; 2: 244-50. doi: 10.24015/JAPM.2015.0033

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