Τίτλος:
Investigating and re-evaluating the role of glycogen synthase kinase 3 beta kinase as a molecular target for cardioprotection by using novel pharmacological inhibitors
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2019 Published on behalf of the European Society of Cardiology.
Συγγραφείς:
Nikolaou, P.-E.
Boengler, K.
Efentakis, P.
Vouvogiannopoulou, K.
Zoga, A.
Gaboriaud-Kolar, N.
Myrianthopoulos, V.
Alexakos, P.
Kostomitsopoulos, N.
Rerras, I.
Tsantili-Kakoulidou, A.
Skaltsounis, A.L.
Papapetropoulos, A.
Iliodromitis, E.K.
Schulz, R.
Andreadou, I.
Περιοδικό:
Cardiovascular Research
Εκδότης:
Oxford University Press
Λέξεις-κλειδιά:
6 bromoindirubin 3' oxime; adenosine triphosphate; autophagy related protein; calcium ion; cyclosporine; glycogen synthase kinase 3 inhibitor; glycogen synthase kinase 3beta; mitochondrial permeability transition pore; mls 2776; mls 2777; mls 2778; mls 2779; reactive oxygen metabolite; unclassified drug; autophagy related protein; carrier protein; cyclophilin D; glycogen synthase kinase 3beta; Gsk3b protein, mouse; mitochondrial permeability transition pore; PPIF protein, mouse; protein kinase inhibitor, animal cell; animal experiment; animal model; animal tissue; Article; controlled study; drug mechanism; drug specificity; drug targeting; enzyme inhibition; enzyme localization; female; heart infarction; heart infarction size; heart protection; hydrolysis; in vitro study; in vivo study; isolated heart; male; mitochondrial respiration; mitochondrion; mouse; myocardial ischemia reperfusion injury; nonhuman; pharmacy (shop); priority journal; rabbit model; upregulation; animal; C57BL mouse; cardiac muscle cell; chemical structure; chemistry; disease model; drug effect; enzymology; genetics; heart infarction; heart mitochondrion; knockout mouse; Leporidae; metabolism; myocardial ischemia reperfusion injury; pathology; signal transduction; structure activity relation, Animals; Autophagy-Related Proteins; Cyclophilin D; Disease Models, Animal; Female; Glycogen Synthase Kinase 3 beta; Isolated Heart Preparation; Male; Mice, Inbred C57BL; Mice, Knockout; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Molecular Structure; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Protein Kinase Inhibitors; Rabbits; Signal Transduction; Structure-Activity Relationship
