Abstract 12855: A New Role of Gsk3b Inhibition in Cardioprotection: A Crucial Regulator of Reticulum-mitochondria Calcium Exchanges
Aims: Glycogen synthase kinase 3 beta (GSK3β) is a multifactorial kinase whose inhibition is required to limit cardiac ischemia-reperfusion injury, but the underlying mechanisms are not clearly defined.
This study tests the hypothesis that GSK3β is localized at the reticulum-mitochondria interface to attenuate mitochondrial calcium overload at reperfusion.
Methods and results: Using cell fractionation of mice heart and proximity ligation assay in cardiac cells models (H9c2 and adult cardiomyocytes), we showed that GSK3β is localized in mitochondrial-associated reticulum membranes in the heart. Furthermore, we showed that GSK3β interacted with the IP3R-Grp75-VDAC calcium channeling complex. Pharmacological (SB216763, 3μM) and genetic inhibition of GSK3β concomitantly reduced its interaction with this calcium channeling complex and inhibited the histamine-stimulated calcium exchange between reticulum and mitochondria.
After hypoxia-reoxygenation, the interaction of GSK3β with the IP3R channeling complex is increased. The GSK3β inhibition at reperfusion limited its interaction with the IP3R channeling complex concomitantly to a SERCA2 activation and IP3R inhibition resulting in an increased reticulum calcium reuptake and lower mitochondrial calcium overload.
Conclusion: Our study indicates for the first time that GSK3β interacts with the IP3R calcium channelling complex at the reticulum-mitochondria interface. Second, our results identify GSK3β as an important regulator of calcium exchange between reticulum and mitochondria at reperfusion.
- © 2013 by American Heart Association, Inc.