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Molecular Pharmacology

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Research ArticleArticle

Activating Transcription Factor 3 Protects against Pressure-Overload Heart Failure via the Autophagy Molecule Beclin-1 Pathway

Heng Lin, Hsiao-Fen Li, Hsi-Hsien Chen, Pei-Fang Lai, Shu-Hui Juan, Jin-Jer Chen and Ching-Feng Cheng
Molecular Pharmacology May 2014, 85 (5) 682-691; DOI: https://doi.org/10.1124/mol.113.090092
Heng Lin
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.L., H.-F.L., S.-H.J.); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C.-F.C.); Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan (H.-H.C.); Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.-H.C.); Department of Emergency Medicine, Tzu Chi General Hospital, Hualien, Taiwan (P.-F.L.); Department of Internal Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (J.-J.C.); and Department of Medical Research, Tzu Chi General Hospital and Department of Pediatrics, Tzu Chi University, Hualien, Taiwan (C.-F.C.)
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Hsiao-Fen Li
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.L., H.-F.L., S.-H.J.); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C.-F.C.); Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan (H.-H.C.); Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.-H.C.); Department of Emergency Medicine, Tzu Chi General Hospital, Hualien, Taiwan (P.-F.L.); Department of Internal Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (J.-J.C.); and Department of Medical Research, Tzu Chi General Hospital and Department of Pediatrics, Tzu Chi University, Hualien, Taiwan (C.-F.C.)
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Hsi-Hsien Chen
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.L., H.-F.L., S.-H.J.); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C.-F.C.); Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan (H.-H.C.); Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.-H.C.); Department of Emergency Medicine, Tzu Chi General Hospital, Hualien, Taiwan (P.-F.L.); Department of Internal Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (J.-J.C.); and Department of Medical Research, Tzu Chi General Hospital and Department of Pediatrics, Tzu Chi University, Hualien, Taiwan (C.-F.C.)
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Pei-Fang Lai
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.L., H.-F.L., S.-H.J.); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C.-F.C.); Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan (H.-H.C.); Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.-H.C.); Department of Emergency Medicine, Tzu Chi General Hospital, Hualien, Taiwan (P.-F.L.); Department of Internal Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (J.-J.C.); and Department of Medical Research, Tzu Chi General Hospital and Department of Pediatrics, Tzu Chi University, Hualien, Taiwan (C.-F.C.)
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Shu-Hui Juan
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.L., H.-F.L., S.-H.J.); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C.-F.C.); Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan (H.-H.C.); Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.-H.C.); Department of Emergency Medicine, Tzu Chi General Hospital, Hualien, Taiwan (P.-F.L.); Department of Internal Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (J.-J.C.); and Department of Medical Research, Tzu Chi General Hospital and Department of Pediatrics, Tzu Chi University, Hualien, Taiwan (C.-F.C.)
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Jin-Jer Chen
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.L., H.-F.L., S.-H.J.); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C.-F.C.); Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan (H.-H.C.); Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.-H.C.); Department of Emergency Medicine, Tzu Chi General Hospital, Hualien, Taiwan (P.-F.L.); Department of Internal Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (J.-J.C.); and Department of Medical Research, Tzu Chi General Hospital and Department of Pediatrics, Tzu Chi University, Hualien, Taiwan (C.-F.C.)
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Ching-Feng Cheng
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.L., H.-F.L., S.-H.J.); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C.-F.C.); Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan (H.-H.C.); Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.-H.C.); Department of Emergency Medicine, Tzu Chi General Hospital, Hualien, Taiwan (P.-F.L.); Department of Internal Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (J.-J.C.); and Department of Medical Research, Tzu Chi General Hospital and Department of Pediatrics, Tzu Chi University, Hualien, Taiwan (C.-F.C.)
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Abstract

Activating transcription factor 3 (ATF3), a cAMP response element-binding protein/ATF family transcription factors member, has been implicated in the cardiovascular and inflammatory system and is rapidly induced by ischemic-reperfusion injuries. We performed transverse aortic banding (TAB) experiments using ATF3 gene-deleted mice (ATF3−/−) and wild-type (WT) mice to determine what effect it might have on heart failure induced by pressure overloading. Compared with the WT mice, ATF3−/− mice were found by echocardiography to have decreased left ventricular contractility with loss of normal cardiac hypertrophic remodeling. The ATF3−/− mice had greater numbers of terminal deoxynucleotidyl transferase–mediated digoxigenin-deoxyuridine nick-end labeling–positive cells and higher levels of activated caspase-3, as well as more apoptosis. Restoration of ATF3 expression in the heart of ATF3−/− mice by adenovirus-induced ATF3 treatment significantly improved cardiac contractility after TAB. The results from molecular and biochemical analyses, including chromatin immune-precipitation and in vitro /in vivo promoter assays, showed that ATF3 bound to the ATF/cAMP response element of the Beclin-1 promoter and that ATF3 reduced autophagy via suppression of the Beclin-1–dependent pathway. Furthermore, infusion of tert-butylhydroquinone (tBHQ), a selective ATF3 inducer, increased the expression of ATF3 via the nuclear factor erythroid 2–related transcriptional factor, inhibited TAB-induced cardiac dilatation, and increased left ventricular contractility, thereby rescuing heart failure. Our study identified a new epigenetic regulation mediated by the stress-inducible gene ATF3 on TAB-induced cardiac dysfunction. These findings suggest that the ATF3 activator tBHQ may have therapeutic potential for the treatment of pressure-overload heart failure induced by chronic hypertension or other pressure overload mechanisms.

Footnotes

    • Received October 5, 2013.
    • Accepted February 18, 2014.
  • H.L. and H.-F.L. contributed equally to this work.

  • This work was supported by grants from the National Science Council, Taiwan [Grant 98-2314-B-320-003] and the Department of Health, Executive Yuan, Taiwan [Grant DOH101-TD-PB-111-NSC013] (to H.L.) and from Tzu Chi General Hospital [Grants TCRD101-10 and TCRD102-17] and Tzu Chi University [Grant TCIRP 99001 and TCIRP102001] (to C.-F.C.).

  • dx.doi.org/10.1124/mol.113.090092.

  • ↵Embedded ImageThis article has supplemental material available at molpharmacol.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (5)
Molecular Pharmacology
Vol. 85, Issue 5
1 May 2014
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Research ArticleArticle

ATF3 Regulates Cardiac Hypertrophy

Heng Lin, Hsiao-Fen Li, Hsi-Hsien Chen, Pei-Fang Lai, Shu-Hui Juan, Jin-Jer Chen and Ching-Feng Cheng
Molecular Pharmacology May 1, 2014, 85 (5) 682-691; DOI: https://doi.org/10.1124/mol.113.090092

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Research ArticleArticle

ATF3 Regulates Cardiac Hypertrophy

Heng Lin, Hsiao-Fen Li, Hsi-Hsien Chen, Pei-Fang Lai, Shu-Hui Juan, Jin-Jer Chen and Ching-Feng Cheng
Molecular Pharmacology May 1, 2014, 85 (5) 682-691; DOI: https://doi.org/10.1124/mol.113.090092
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