Ischemic postconditioning (IPCD) has been shown to reduce myocardial infarct size through activation of survival kinases such as Akt, ERK 1/2 as well as their common target p70S6K1, and AMPK during the early minutes of reperfusion. However, most of these results were obtained using “healthy” animals and the state of corresponding phosphatases has never been investigated in the contexte of obesity. Thus, the aims of this study were to establish whether the efficiency of IPCD is maintained in obese heart and to explore kinases but also phosphatases in this context.
The effects of IPCD were investigated in 8-10 weeks old leptin-deficient obese (ob/ob) mice and C57BL/6J (WT) mice wereused as control. All animals underwent 30min of coronary artery occlusion followed by 24h of reperfusion associated or not with IPCD (6 cycles of 10 s occlusion/10 s reperfusion). Additional mice were sacrificed at 10min of reperfusion for western blot analysis of P-Akt, P-ERK 1/2, P-p70S6K1, P-AMPK and the respective phosphatases PTEN, PP2C and MKP-3.
In WT mice, IPCD reduced infarct size by 58 % (33±1 % vs 14±3 % for control and IPCD, respectively, p<0.05) and simultaneously increased the phosphorylated forms of Akt, ERK 1/2, p70S6K1 and AMPK but decreased cytosolic PTEN, MKP-3 and PP2C levels. In contrast, in ob/ob mice, IPCD failed to induce cardioprotection (53±4 %vs56±5 % for infarct sizes in control and IPCD, respectively) and did not increase the phosphorylation state of all these kinases. Interestingly, the level of these coresponding phosphatases were simultaneously increased.
Although IPCD reduces myocardial infarct size in healthy animals, its cardioprotective effect vanishes with obesity. The increase in PTEN, MKP-3 and PP2C levels might partly explain the lack of enhanced phosphorylation by IPCD of Akt, ERK1/2, p70S6K1 or AMPK and therefore, the loss of cardioprotection in this experimental model of obesity.
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