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Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse

Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse
Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse
The inactivation of glycogen synthase kinase-3? (GSK-3?) is proposed as the event integrating protective pathways initiated by preconditioning and other interventions. The inactivation of GSK-3 is thought to decrease the probability of opening of the mitochondrial permeability transition pore. The aim of this study was to verify the role of GSK-3 using a targeted mouse line lacking the critical N-terminal serine within GSK-3? (Ser9) and the highly homologous GSK-3 (Ser21), which when phosphorylated results in kinase inactivation. Postconditioning with 10 cycles of 5 seconds of reperfusion/5 seconds of ischemia and preconditioning with 6 cycles of 4 minutes of ischemia/6 minutes of reperfusion, similarly reduced infarction of the isolated perfused mouse heart in response to 30 minutes of global ischemia and 120 minutes of reperfusion. Preconditioning caused noticeable inactivating phosphorylation of GSK-3. However, both preconditioning and postconditioning still protected hearts of homozygous GSK-3 double knockin mice. Moreover, direct pharmacological inhibition of GSK-3 catalytic activity with structurally diverse inhibitors before or after ischemia failed to recapitulate conditioning protection. Nonetheless, cyclosporin A, a direct mitochondrial permeability transition pore inhibitor, reduced infarction in hearts from both wild-type and homozygous GSK-3 double knockin mice. Furthermore, in adult cardiac myocytes from GSK-3 double knockin mice, insulin exposure was still as effective as cyclosporin A in delaying mitochondrial permeability transition pore opening. Our results, which include a novel genetic approach, suggest that the inhibition of GSK-3 is unlikely to be the key determinant of cardioprotective signaling in either preconditioning or postconditioning in the mouse.
postconditioniong, preconditioning, GSK-3, mPTP
0009-7330
307-14
Nishino, Yasuhiro
dc63108e-e96b-4afa-9428-0d45ac6c331f
Webb, Ian G.
5417f778-9c53-4086-831f-c35a8d0dc9e2
Davidson, Sean M.
b8eeed87-5d86-42ca-8844-25bf6887253c
Ahmed, Aminul
175a1358-5255-4f20-8cf9-96fac237bc9f
Clark, James E.
3d537ae9-2bb8-44d5-bbe2-68e0f73e705c
Jacquet, Sebastien
fc7e5eeb-8108-43ca-a7e0-87293612846e
Shah, Ajay M.
20c6e370-6389-46f5-9673-c68712df43a1
Miura, Tetsuji
59f91b36-e700-4680-9bc9-6191f529b404
Yellon, Derek M.
9eed4a3f-5085-42ca-b59e-f50b8006a9e3
Avkiran, Metin
eefa0cfe-f240-48cd-ba61-b68c45f170e7
Marber, Michael S.
ff387cdb-b430-41f8-854f-15857b88d919
Nishino, Yasuhiro
dc63108e-e96b-4afa-9428-0d45ac6c331f
Webb, Ian G.
5417f778-9c53-4086-831f-c35a8d0dc9e2
Davidson, Sean M.
b8eeed87-5d86-42ca-8844-25bf6887253c
Ahmed, Aminul
175a1358-5255-4f20-8cf9-96fac237bc9f
Clark, James E.
3d537ae9-2bb8-44d5-bbe2-68e0f73e705c
Jacquet, Sebastien
fc7e5eeb-8108-43ca-a7e0-87293612846e
Shah, Ajay M.
20c6e370-6389-46f5-9673-c68712df43a1
Miura, Tetsuji
59f91b36-e700-4680-9bc9-6191f529b404
Yellon, Derek M.
9eed4a3f-5085-42ca-b59e-f50b8006a9e3
Avkiran, Metin
eefa0cfe-f240-48cd-ba61-b68c45f170e7
Marber, Michael S.
ff387cdb-b430-41f8-854f-15857b88d919

Nishino, Yasuhiro, Webb, Ian G., Davidson, Sean M., Ahmed, Aminul, Clark, James E., Jacquet, Sebastien, Shah, Ajay M., Miura, Tetsuji, Yellon, Derek M., Avkiran, Metin and Marber, Michael S. (2008) Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse. Circulation Research, 1 (103), 307-14. (doi:10.1161/CIRCRESAHA.107.169953).

Record type: Article

Abstract

The inactivation of glycogen synthase kinase-3? (GSK-3?) is proposed as the event integrating protective pathways initiated by preconditioning and other interventions. The inactivation of GSK-3 is thought to decrease the probability of opening of the mitochondrial permeability transition pore. The aim of this study was to verify the role of GSK-3 using a targeted mouse line lacking the critical N-terminal serine within GSK-3? (Ser9) and the highly homologous GSK-3 (Ser21), which when phosphorylated results in kinase inactivation. Postconditioning with 10 cycles of 5 seconds of reperfusion/5 seconds of ischemia and preconditioning with 6 cycles of 4 minutes of ischemia/6 minutes of reperfusion, similarly reduced infarction of the isolated perfused mouse heart in response to 30 minutes of global ischemia and 120 minutes of reperfusion. Preconditioning caused noticeable inactivating phosphorylation of GSK-3. However, both preconditioning and postconditioning still protected hearts of homozygous GSK-3 double knockin mice. Moreover, direct pharmacological inhibition of GSK-3 catalytic activity with structurally diverse inhibitors before or after ischemia failed to recapitulate conditioning protection. Nonetheless, cyclosporin A, a direct mitochondrial permeability transition pore inhibitor, reduced infarction in hearts from both wild-type and homozygous GSK-3 double knockin mice. Furthermore, in adult cardiac myocytes from GSK-3 double knockin mice, insulin exposure was still as effective as cyclosporin A in delaying mitochondrial permeability transition pore opening. Our results, which include a novel genetic approach, suggest that the inhibition of GSK-3 is unlikely to be the key determinant of cardioprotective signaling in either preconditioning or postconditioning in the mouse.

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More information

Published date: 26 June 2008
Keywords: postconditioniong, preconditioning, GSK-3, mPTP
Organisations: University of Southampton

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Local EPrints ID: 142873
URI: http://eprints.soton.ac.uk/id/eprint/142873
ISSN: 0009-7330
PURE UUID: 85c0c7bd-abd4-4672-bbc2-78a38cd3ca6e

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Date deposited: 01 Apr 2010 11:56
Last modified: 17 Jul 2019 00:08

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Contributors

Author: Yasuhiro Nishino
Author: Ian G. Webb
Author: Sean M. Davidson
Author: Aminul Ahmed
Author: James E. Clark
Author: Sebastien Jacquet
Author: Ajay M. Shah
Author: Tetsuji Miura
Author: Derek M. Yellon
Author: Metin Avkiran
Author: Michael S. Marber

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