Akt mediates 17 beta-estradiol and/or estrogen receptor-alpha inhibition of LPS-induced tumor necresis factor-alpha expression and myocardial cell apoptosis by suppressing the JNK1/2-NF kappa B pathway

作者：Liu Chung Jung; Lo Jeng Fan; Kuo Chia Hua; Chu Chun Hsien; Chen Li Ming; Tsai Fuu Jen; Tsai Chang Hai; Tzang Bor Show; Kuo Wei Wen; Huang Chih Yang^*

来源：JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2009, 13(9B): 3655-3667.

DOI：10.1111/j.1582-4934.2009.00669.x

• myocardial cell apoptosis
• 17 beta-estradiol
• estrogen receptor-alpha
• PI3K
• Akt
• NF kappa B
• I kappa B
• JNK
• lipopolysacchride

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

• 出版日期2009-9
• 单位中国医科大学; 河北医科大学