PT - JOURNAL ARTICLE AU - Heng Lin AU - Hsiao-Fen Li AU - Hsi-Hsien Chen AU - Pei-Fang Lai AU - Shu-Hui Juan AU - Jin-Jer Chen AU - Ching-Feng Cheng TI - Activating Transcription Factor 3 Protects against Pressure-Overload Heart Failure via the Autophagy Molecule Beclin-1 Pathway AID - 10.1124/mol.113.090092 DP - 2014 May 01 TA - Molecular Pharmacology PG - 682--691 VI - 85 IP - 5 4099 - http://molpharm.aspetjournals.org/content/85/5/682.short 4100 - http://molpharm.aspetjournals.org/content/85/5/682.full SO - Mol Pharmacol2014 May 01; 85 AB - 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.