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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Evidence shows that women have lower tumour necrosis factor-α (TNF-α) 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 17β-estradiol (E2) and estrogen receptor α (ERα) on LPS-induced apoptosis by analyzing the activation of survival and death signalling pathways in doxycycline (Dox)-inducible Tet-On/ERα H9c2 myocardial cells and ERα-transfected primary cardiomyocytes overexpressing ERα. We found that LPS challenge activated JNK1/2, and then induced IκB degradation, NFκB activation, TNF-α up-regulation and subsequent myocardial apoptotic responses. In addition, treatments involving E2, membrane-impermeable BSA-E2 and/or Dox, which induces ERα overexpression, significantly inhibited LPS-induced apoptosis by suppressing LPS-up-regulated JNK1/2 activity, IκB degradation, NFκB activation and pro-apoptotic proteins (e.g. TNF-α, 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 ERα 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 ERα expression exert their cardioprotective effects by inhibiting JNK1/2-mediated LPS-induced TNF-α expression and cardiomyocyte apoptosis through activation of Akt.

Original languageEnglish
Pages (from-to)3655-3667
Number of pages13
JournalJournal of Cellular and Molecular Medicine
Volume13
Issue number9 B
DOIs
StatePublished - Sep 2009

Keywords

  • 17β-estradiol
  • Estrogen receptor-α
  • IκB
  • JNK
  • Lipopolysacchride
  • Myocardial cell apoptosis
  • NFκB
  • PI3K/Akt

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