Mocanu Mihaela M, Yellon Derek M
The Hatter Institute and Centre for Cardiology, University College London Medical School, London WC1E 6DB, UK.
FEBS Lett. 2003 Dec 4;555(2):302-6. doi: 10.1016/s0014-5793(03)01260-2.
Ischaemic preconditioning is associated with the activation of prosurvival mechanisms. Here we demonstrate that following a preconditioning protocol, the proapoptotic p53 is inactivated possibly via phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-murine double minute 2 (Mdm2) phosphorylation. Our data show that in preconditioned hearts Mdm2 was significantly phosphorylated, and wortmannin (a PI3K inhibitor) abrogated this effect (Western blotting). Also in preconditioned hearts p53 was shown to be bound to phospho-Mdm2 (co-immunoprecipitation). Furthermore, pifithrin alpha (a p53 inhibitor), administered to isolated perfused hearts prior to ischaemia, significantly attenuated the infarction. In conclusion our results suggest that p53 is implicated in ischaemia/reperfusion injury and that preconditioning counterbalances this effect via PI3K-Akt-Mdm2 phosphorylation.
缺血预处理与促生存机制的激活有关。在此我们证明，遵循预处理方案后，促凋亡的p53可能通过磷脂酰肌醇3激酶（PI3K）-蛋白激酶B（Akt）-小鼠双微体2（Mdm2）磷酸化而失活。我们的数据显示，在预处理的心脏中，Mdm2被显著磷酸化，渥曼青霉素（一种PI3K抑制剂）消除了这种效应（蛋白质印迹法）。同样在预处理的心脏中，p53被证明与磷酸化的Mdm2结合（免疫共沉淀法）。此外，在缺血前给予离体灌注心脏pifithrin alpha（一种p53抑制剂），可显著减轻梗死。总之，我们的结果表明，p53与缺血/再灌注损伤有关，且预处理通过PI3K-Akt-Mdm2磷酸化来抵消这种效应。
