Published online before print June 26, 2008, doi: 10.1161/CIRCRESAHA.107.169953
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on December 13, 2007
Revised on June 9, 2008
Accepted on June 12, 2008
Glycogen Synthase Kinase-3 Inactivation Is Not Required for Ischemic Preconditioning or Postconditioning in the Mouse
Yasuhiro Nishino ;
From the King's College London BHF Centre (Y.N., I.G.W., A.I.A., J.E.C., S.J., A.M.S., M.A., M.S.M.), Cardiovascular Division, The Rayne Institute, St. Thomas' Hospital, UK; The Hatter Cardiovascular Institute (S.M.D., D.M.Y.), University College London Hospital and Medical School, UK; and Second Department of Internal Medicine (T.M.), Sapporo Medical University School of Medicine, Japan.
* To whom correspondence should be addressed. E-mail: mike.marber{at}kcl.ac.uk.
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.
Key words: postconditioniong • preconditioning • GSK-3 • mPTP
Related Article:
- Does Inhibition of Glycogen Synthase Kinase Protect in Mice?
- Elizabeth Murphy and Charles Steenbergen
Circ. Res. 2008 103: 226-228.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  L. Lacerda, S. Somers, L. H. Opie, and S. Lecour Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway Cardiovasc Res, November 1, 2009; 84(2): 201 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch No RISK, no ... cardioprotection? A critical perspective Cardiovasc Res, November 1, 2009; 84(2): 173 - 175. [Full Text] [PDF]
|
|
|
|
|
|
J. Musiolik, P. van Caster, A. Skyschally, K. Boengler, P. Gres, R. Schulz, and G. Heusch Reduction of infarct size by gentle reperfusion without activation of reperfusion injury salvage kinases in pigs Cardiovasc Res, August 25, 2009; (2009) cvp271v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sicard, S. Jacquet, K. S. Kobayashi, R. A. Flavell, and M. S. Marber Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1 Cardiovasc Res, July 15, 2009; 83(2): 277 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Granfeldt, D. J. Lefer, and J. Vinten-Johansen Protective ischaemia in patients: preconditioning and postconditioning Cardiovasc Res, July 15, 2009; 83(2): 234 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Juhaszova, D. B. Zorov, Y. Yaniv, H. B. Nuss, S. Wang, and S. J. Sollott Role of Glycogen Synthase Kinase-3{beta} in Cardioprotection Circ. Res., June 5, 2009; 104(11): 1240 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Miyamoto, M. Rubio, and M. A. Sussman Nuclear and mitochondrial signalling Akts in cardiomyocytes Cardiovasc Res, May 1, 2009; 82(2): 272 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Skyschally, P. van Caster, K. Boengler, P. Gres, J. Musiolik, D. Schilawa, R. Schulz, and G. Heusch Ischemic Postconditioning in Pigs: No Causal Role for RISK Activation Circ. Res., January 2, 2009; 104(1): 15 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zhai and J. Sadoshima Overcoming an Energy Crisis?: An Adaptive Role of Glycogen Synthase Kinase-3 Inhibition in Ischemia/Reperfusion Circ. Res., October 24, 2008; 103(9): 910 - 913. [Full Text] [PDF]
|
|
|
|
|
|
M. Tanno and T. Miura Adenine nucleotide translocator, a mitochondrial carrier protein, and fate of cardiomyocytes after ischaemia/reperfusion Cardiovasc Res, October 1, 2008; 80(1): 1 - 2. [Full Text] [PDF]
|
|
|
|
|
|
E. Murphy and C. Steenbergen Does Inhibition of Glycogen Synthase Kinase Protect in Mice? Circ. Res., August 1, 2008; 103(3): 226 - 228. [Full Text] [PDF]
|
|