Open AccessThe Akt1 isoform is an essential mediator of ischaemic preconditioning
Author(s) -
Kunuthur Suma P.,
Mocanu Mihaela M.,
Hemmings Brian A.,
Hausenloy Derek J.,
Yellon Derek M.
Publication year - 2012
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2011.01491.x
Subject(s) - cardioprotection , akt1 , protein kinase b , akt2 , phosphorylation , pi3k/akt/mtor pathway , ischemic preconditioning , medicine , ischemia , chemistry , pharmacology , signal transduction , biochemistry
Phosphatidyl‐inositol‐3‐kinase (PI3K)‐Akt pathway is essential for conferring cardioprotection in response to ischaemic preconditioning (IPC) stimulus. However, the role of the individual Akt isoforms expressed in the heart in mediating the protective response to IPC is unknown. In this study, we investigated the specific contribution of Akt1 and Akt2 in cardioprotection against ischaemia‐reperfusion (I‐R) injury. Mice deficient in Akt1 or Akt2 were subjected to in vivo regional myocardial ischaemia for 30 min. followed by reperfusion for 2 hrs with or without a prior IPC stimulus. Our results show that mice deficient in Akt1 were resistant to protection with either one or three cycles of IPC stimulus (42.7 ± 6.5% control versus 38.5 ± 1.9% 1 χ IPC, N = 6, NS; 41.4 ± 6.3% control versus 32.4 ± 3.2% 3 χ IPC, N = 10, NS). Western blot analysis, performed on heart samples taken from Akt1 −/− mice subjected to IPC, revealed an impaired phosphorylation of GSK‐3β, a downstream effector of Akt, as well as Erk1/2, the parallel component of the reperfusion injury salvage kinase pathway. Akt2 −/− mice, which exhibit a diabetic phenotype, however, were amenable to protection with three but not one cycle of IPC (46.4 ± 5.6% control versus 35.9 ± 5.0% in 1 χ IPC, N = 6, NS; 47.0 ± 6.0% control versus 30.8 ± 3.3% in 3 χ IPC, N = 6; * P = 0.039). Akt1 but not Akt2 is essential for mediating a protective response to an IPC stimulus. Impaired activation of GSK‐3β and Erk1/2 might be responsible for the lack of protective response to IPC in Akt1 −/− mice. The rise in threshold for protection in Akt2 −/− mice might be due to their diabetic phenotype.