title: Activating transcription factor 3 protects against pressure-overload heart failure via the autophagy molecule Beclin-1 pathway.
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.
authors.affiliation: 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.).
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.forename: Hsiao-Fen
authors.initials: HF
authors.lastname: Li
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Chen
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Lai
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Juan
authors.forename: Jin-Jer
authors.initials: JJ
authors.lastname: Chen
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Cheng
mesh_terms: D051700:Activating Transcription Factor 3 / Q000819:agonists / Q000096:biosynthesis*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071186:Beclin-1; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D057809:HEK293 Cells; D006333:Heart Failure / Q000378:metabolism* / Q000517:prevention & control*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D051700:Activating Transcription Factor 3; D051017:Apoptosis Regulatory Proteins; C103002:Atf3 protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D002316:Cardiotonic Agents; D006873:Hydroquinones; C018855:2-tert-butylhydroquinone