Akt mediates 17β-estradiol and/or estrogen receptor-α inhibition of LPS-induced tumor necresis factor-α expression and myocardial cell apoptosis by suppressing the JNK1/2-NFκB pathway

Evidence shows that women have lower tumour necrosis factor(TNF) levels and lower incidences of heart dysfunction and sepsis-related morbidity and mortality. To identify the cardioprotective effects and precise cellular/molecular mechanisms behind estrogen and estrogen receptors (ERs), we investigated the effects of 17 -estradiol (E2) and estrogen receptor (ER ) on LPS-induced apoptosis by analyzing the activation of survival and death signalling pathways in doxycycline (Dox)-inducible Tet-On/ER H9c2 myocardial cells and ER -transfected primary cardiomyocytes overexpressing ER . We found that LPS challenge activated JNK1/2, and then induced I B degradation, NF B activation, TNFup-regulation and subsequent myocardial apoptotic responses. In addition, treatments involving E2, membrane-impermeable BSA-E2 and/or Dox, which induces ER overexpression, significantly inhibited LPS-induced apoptosis by suppressing LPS-up-regulated JNK1/2 activity, I B degradation, NF B activation and pro-apoptotic proteins (e.g. TNF, active caspases-8, t-Bid, Bax, released cytochrome c, active caspase-9, active caspase-3) in myocardial cells. However, the cardioprotective properties of E2, BSA-E2 and ER overexpression to inhibit LPS-induced apoptosis and promote cell survival were attenuated by applying LY294002 (PI3K inhibitor) and PI3K siRNA. These findings suggest that E2, BSA-E2 and ER expression exert their cardioprotective effects by inhibiting JNK1/2-mediated LPS-induced TNFexpression and cardiomyocyte apoptosis through activation of Akt.