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: Heng Lin, Hsiao-Fen Li, Hsi-Hsien Chen, Pei-Fang Lai, Shu-Hui Juan, Jin-Jer Chen, Ching-Feng Cheng
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 85 Issue 5 Pg. 682-91 (May 2014) ISSN: 1521-0111 [Electronic] United States
• PMID: 24550138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Activating Transcription Factor 3
• Apoptosis Regulatory Proteins
• Atf3 protein, mouse
• Beclin-1
• Becn1 protein, mouse
• Cardiotonic Agents
• Hydroquinones
• 2-tert-butylhydroquinone

Topics

• Activating Transcription Factor 3 (agonists, biosynthesis)
• Animals
• Apoptosis Regulatory Proteins (antagonists & inhibitors, biosynthesis)
• Autophagy (drug effects, physiology)
• Beclin-1
• Cardiotonic Agents (therapeutic use)
• HEK293 Cells
• Heart Failure (metabolism, prevention & control)
• Humans
• Hydroquinones (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Signal Transduction (drug effects, physiology)
• Ventricular Function, Left (drug effects, physiology)