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Inhibition of PI3K survival pathway by LY294002 augments p53‐mediated myocyte apoptosis in myocardial ischemia reperfusion (MI/R)
Author(s) -
Hock Carl E.,
Xu Baohuan,
Cavalieri Thomas A.,
Liu Peitan
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.793.12
Subject(s) - ly294002 , apoptosis , cardiac function curve , pi3k/akt/mtor pathway , medicine , ischemia , myocardial infarction , reperfusion injury , myocyte , endocrinology , cardiac myocyte , cardiology , pharmacology , chemistry , heart failure , biochemistry
Ischemic preconditioning limits infarct size, indicating that cell‐adaptive behavior can protect cardiac cells from severe ischemic injury. This adaptive behavior can be pharmacologically modulated by activation of phosphoinositide 3‐OH kinase (PI3K) survival pathway. We have previously demonstrated that inhibition of p53 transcription with pifithrin‐alpha improves cardiac function and reduces myocyte apoptosis in aged rats following myocardial ischemia‐reperfusion (MI/R). LY294002 (an inhibitor of PI3K, 10 μM, 2 ml/kg bw, iv) or vehicle (2 ml/kg bw) were administered to male F344 young and aged rats subjected to 30 min of myocardial ischemia followed by 4 hours of reperfusion. Pretreatment of MI/R rats with LY294002 significantly increased DNA fragmentation in the area‐at‐risk, worsened cardiac output index and mean arterial blood pressure compared to MI/R rats treated with vehicle. Analysis of Western blots indicated that inhibition of PI3K by LY294002 decreased Mdm2 expression and increased expression of p53 and pospho‐p53 (Ser15). These data indicate that the PI3K survival pathway is active in MI/R in both young and aged rats and suggests that activation of this pathway may represent an important strategy to improve the recovery of cardiac function following MI/R.