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Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
Published on: July 27, 2022
Activating transcription factor 3 protects against pressure-overload heart failure via the autophagy molecule
Heng Lin1, Hsiao-Fen Li, Hsi-Hsien Chen
1Department 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.).
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.
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