TY - JOUR
T1 - Investigating and re-evaluating the role of glycogen synthase kinase 3 beta kinase as a molecular target for cardioprotection by using novel pharmacological inhibitors
AU - Nikolaou, Panagiota Efstathia
AU - Boengler, Kerstin
AU - Efentakis, Panagiotis
AU - Vouvogiannopoulou, Konstantina
AU - Zoga, Anastasia
AU - Gaboriaud-Kolar, Nicholas
AU - Myrianthopoulos, Vassilios
AU - Alexakos, Pavlos
AU - Kostomitsopoulos, Nikolaos
AU - Rerras, Ioannis
AU - Tsantili-Kakoulidou, Anna
AU - Skaltsounis, Alexios Leandros
AU - Papapetropoulos, Andreas
AU - Iliodromitis, Efstathios K.
AU - Schulz, Rainer
AU - Andreadou, Ioanna
N1 - Publisher Copyright:
© 2019 Published on behalf of the European Society of Cardiology.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Aims: Glycogen synthase kinase 3 beta (GSK3β) link with the mitochondrial Permeability Transition Pore (mPTP) in cardioprotection is debated. We investigated the role of GSK3β in ischaemia (I)/reperfusion (R) injury using pharmacological tools. Methods and results: Infarct size using the GSK3β inhibitor BIO (6-bromoindirubin-3′-oxime) and several novel analogues (MLS2776-MLS2779) was determined in anaesthetized rabbits and mice. In myocardial tissue GSK3β inhibition and the specificity of the compounds was tested. The mechanism of protection focused on autophagy-related proteins. GSK3β localization was determined in subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) isolated from Langendorff-perfused murine hearts (30'I/10'R or normoxic conditions). Calcium retention capacity (CRC) was determined in mitochondria after administration of the inhibitors in mice and in vitro. The effects of the inhibitors on mitochondrial respiration, reactive oxygen species (ROS) formation, ATP production, or hydrolysis were measured in SSM at baseline. Cyclosporine A (CsA) was co-administered with the inhibitors to address putative additive cardioprotective effects. Rabbits and mice treated with MLS compounds had smaller infarct size compared with control. In rabbits, MLS2776 and MLS2778 possessed greater infarct-sparing effects than BIO. GSK3β inhibition was confirmed at the 10th min and 2 h of reperfusion, while up-regulation of autophagy-related proteins was evident at late reperfusion. The mitochondrial amount of GSK3β was similar in normoxic SSM and IFM and was not altered by I/R. The inhibitors did not affect CRC or respiration, ROS and ATP production/hydrolysis at baseline. The co-administration of CsA ensured that cardioprotection was CypD-independent. Conclusion: Pharmacological inhibition of GSK3β attenuates infarct size beyond mPTP inhibition.
AB - Aims: Glycogen synthase kinase 3 beta (GSK3β) link with the mitochondrial Permeability Transition Pore (mPTP) in cardioprotection is debated. We investigated the role of GSK3β in ischaemia (I)/reperfusion (R) injury using pharmacological tools. Methods and results: Infarct size using the GSK3β inhibitor BIO (6-bromoindirubin-3′-oxime) and several novel analogues (MLS2776-MLS2779) was determined in anaesthetized rabbits and mice. In myocardial tissue GSK3β inhibition and the specificity of the compounds was tested. The mechanism of protection focused on autophagy-related proteins. GSK3β localization was determined in subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) isolated from Langendorff-perfused murine hearts (30'I/10'R or normoxic conditions). Calcium retention capacity (CRC) was determined in mitochondria after administration of the inhibitors in mice and in vitro. The effects of the inhibitors on mitochondrial respiration, reactive oxygen species (ROS) formation, ATP production, or hydrolysis were measured in SSM at baseline. Cyclosporine A (CsA) was co-administered with the inhibitors to address putative additive cardioprotective effects. Rabbits and mice treated with MLS compounds had smaller infarct size compared with control. In rabbits, MLS2776 and MLS2778 possessed greater infarct-sparing effects than BIO. GSK3β inhibition was confirmed at the 10th min and 2 h of reperfusion, while up-regulation of autophagy-related proteins was evident at late reperfusion. The mitochondrial amount of GSK3β was similar in normoxic SSM and IFM and was not altered by I/R. The inhibitors did not affect CRC or respiration, ROS and ATP production/hydrolysis at baseline. The co-administration of CsA ensured that cardioprotection was CypD-independent. Conclusion: Pharmacological inhibition of GSK3β attenuates infarct size beyond mPTP inhibition.
KW - Glycogen synthase kinase 3 beta (gsk3β)
KW - Infarct size
KW - Mitochondrial permeability transition pore
KW - Novel selective analogues of bio
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U2 - 10.1093/cvr/cvz061
DO - 10.1093/cvr/cvz061
M3 - Article
C2 - 30843027
AN - SCOPUS:85066472125
SN - 0008-6363
VL - 115
SP - 1228
EP - 1243
JO - Cardiovascular research
JF - Cardiovascular research
IS - 7
ER -