Oestrogen prevents cardiomyocyte apoptosis by suppressing p38α-mediated activation of p53 and by down-regulating p53 inhibition on p38β.

AIMS we have previously shown that 17-β-estradiol (E2) protects cardiomyocytes exposed to simulated ischaemia-reperfusion (I/R) by differentially regulating pro-apoptotic p38α mitogen-activated protein kinase (p38α MAPK) and pro-survival p38β. However, little is known about how E2 modulation of these kinases alters apoptotic signalling. An attractive downstream target is p53, a well-known mediator of apoptosis and a substrate of p38α MAPK. The aim of this study was to determine whether the cytoprotective actions of oestrogen involve regulation of p53 via cardiac p38 MAPKs. METHODS AND RESULTS cultured rat cardiomyocytes underwent hypoxia followed by reoxygenation (H/R) to simulate I/R. We found that inhibiting p53 significantly reduced apoptosis. Phosphorylation of p53 at serine 15 [p-p53(S15)] increased after H/R in a p38α MAPK- and reactive oxygen species (ROS)-dependent manner. E2 at 10 nM effectively inhibited p-p53(S15) and mitochondrial translocation of p53. Blocking p53 led to augmented p38β activity and attenuated ROS, suggesting suppression of this antioxidant kinase by p53. The use of a specific agonist for each oestrogen receptor (ER) isoform, ERα and ERβ, demonstrated that both isoforms participate in preventing cell death by inhibiting p53 in the mitochondria-centred apoptotic processes. CONCLUSION our results demonstrate that during H/R stress, cardiomyocytes undergo p53-dependent apoptosis following phosphorylation of p53 by p38α MAPK, leading to p38β suppression. E2 protects cardiomyocytes by inhibiting p38α-p53 signalling in apoptosis.