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Estrogen and/or Estrogen Receptor α Inhibits BNIP3-Induced Apoptosis and Autophagy in H9c2 Cardiomyoblast Cells

School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung 404, Taiwan
Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan
Department of Health and Nutrition Biotechnology, Asia University, Taichung 404, Taiwan
School of Chinese Medicine, China Medical University, Taichung 413, Taiwan
Department of Nursing, MeiHo University, Pingtung 912, Taiwan
Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan
Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management College, Taipei 11260, Taiwan
Department of Biotechnology, Bharathiar University, Coimbatore 641 046, India
Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan
Division of Cardiology, China Medical University Hospital, Taichung 404, Taiwan
Department of Biological Science and Technology, Asia University, Taichung 404, Taiwan
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(5), 1298;
Received: 23 February 2018 / Revised: 15 April 2018 / Accepted: 23 April 2018 / Published: 26 April 2018
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
PDF [2492 KB, uploaded 3 May 2018]


The process of autophagy in heart cells maintains homeostasis during cellular stress such as hypoxia by removing aggregated proteins and damaged organelles and thereby protects the heart during the times of starvation and ischemia. However, autophagy can lead to substantial cell death under certain circumstances. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a hypoxia-induced marker, has been shown to induce both autophagy and apoptosis. A BNIP3-docked organelle, e.g., mitochondria, also determines whether autophagy or apoptosis will take place. Estrogen (E2) and estrogen receptor (ER) alpha (ERα) have been shown to protect the heart against mitochondria-dependent apoptosis. The aim of the present study is to investigate the mechanisms by which ERα regulates BNIP3-induced apoptosis and autophagy, which is associated with hypoxic injury, in cardiomyoblast cells. An in vitro model to mimic hypoxic injury in the heart by engineering H9c2 cardiomyoblast cells to overexpress BNIP3 was established. Further, the effects of E2 and ERα in BNIP3-induced apoptosis and autophagy were determined in BNIP3 expressing H9c2 cells. Results from TUNEL assay and Immunoflourecense assay for LC3 puncta formation, respectively, revealed that ERα/E2 suppresses BNIP3-induced apoptosis and autophagy. The Western blot analysis showed ERα/E2 decreases the protein levels of caspase 3 (apoptotic marker), Atg5, and LC3-II (autophagic markers). Co-immunoprecipitation of BNIP3 and immunoblotting of Bcl-2 and Rheb showed that ERα reduced the interaction between BNIP3 and Bcl-2 or Rheb. The results confirm that ERα binds to BNIP3 causing a reduction in the levels of functional BNIP3 and thereby inhibits cellular apoptosis and autophagy. In addition, ERα attenuated the activity of the BNIP3 promoter by binding to SP-1 or NFκB sites. View Full-Text
Keywords: BNIP3; estrogen receptor alpha; apoptosis; autophagy BNIP3; estrogen receptor alpha; apoptosis; autophagy

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Chen, B.-C.; Weng, Y.-J.; Shibu, M.A.; Han, C.-K.; Chen, Y.-S.; Shen, C.-Y.; Lin, Y.-M.; Viswanadha, V.P.; Liang, H.-Y.; Huang, C.-Y. Estrogen and/or Estrogen Receptor α Inhibits BNIP3-Induced Apoptosis and Autophagy in H9c2 Cardiomyoblast Cells. Int. J. Mol. Sci. 2018, 19, 1298.

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