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
Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan
Search for more papers by this authorJeng-Fan Lo
Department of Oncology and Molecular Medicine, National Yang-Mine University, Taipei, Taiwan
Search for more papers by this authorChia-Hua Kuo
Laboratory of Exercise Biochemistry, Taipei Physical Education College, Taipei, Taiwan
Search for more papers by this authorChun-Hsien Chu
Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan
Search for more papers by this authorLi-Ming Chen
Departments of Internal Medicine, Armed Force Taichung General Hospital, Taichung, Taiwan
Search for more papers by this authorFuu-Jen Tsai
Department of Pediatrics, Medical Research and Medical Genetics, China Medical University, Taichung, Taiwan
Search for more papers by this authorChang-Hai Tsai
Department of Healthcare Administration, Asia University, Taichung, Taiwan
Search for more papers by this authorBor-Show Tzang
Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
These authors contributed equally to this paper.
Search for more papers by this authorWei-Wen Kuo
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
These authors contributed equally to this paper.
Search for more papers by this authorCorresponding Author
Chih-Yang Huang
Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan
Institute of Medical Science, China Medical University, Taichung, Taiwan
Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
These authors contributed equally to this paper.
Correspondence to: Chih-YANG HUANG, Ph.D., Graduate Institute of Chinese Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404, Taiwan.Tel.: +886-4-22053366 ext. 3313.Fax: 886-4-2207-0465E-mail: [email protected]Search for more papers by this authorChung-Jung Liu
Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan
Search for more papers by this authorJeng-Fan Lo
Department of Oncology and Molecular Medicine, National Yang-Mine University, Taipei, Taiwan
Search for more papers by this authorChia-Hua Kuo
Laboratory of Exercise Biochemistry, Taipei Physical Education College, Taipei, Taiwan
Search for more papers by this authorChun-Hsien Chu
Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan
Search for more papers by this authorLi-Ming Chen
Departments of Internal Medicine, Armed Force Taichung General Hospital, Taichung, Taiwan
Search for more papers by this authorFuu-Jen Tsai
Department of Pediatrics, Medical Research and Medical Genetics, China Medical University, Taichung, Taiwan
Search for more papers by this authorChang-Hai Tsai
Department of Healthcare Administration, Asia University, Taichung, Taiwan
Search for more papers by this authorBor-Show Tzang
Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
These authors contributed equally to this paper.
Search for more papers by this authorWei-Wen Kuo
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
These authors contributed equally to this paper.
Search for more papers by this authorCorresponding Author
Chih-Yang Huang
Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan
Institute of Medical Science, China Medical University, Taichung, Taiwan
Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
These authors contributed equally to this paper.
Correspondence to: Chih-YANG HUANG, Ph.D., Graduate Institute of Chinese Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404, Taiwan.Tel.: +886-4-22053366 ext. 3313.Fax: 886-4-2207-0465E-mail: [email protected]Search for more papers by this authorAbstract
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.
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