Histone deacetylase inhibition improved cardiac functions with direct antifibrotic activity in heart failure Yu-Hsun Kao a,b , Jing-Ping Liou c , Cheng-Chich Chung b,d , Gi-Shih Lien e , Ching-Chuan Kuo f , Shih-Ann Chen g,h , Yi-Jen Chen b,d, ⁎ a Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan b Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan c School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan d Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan e Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan f Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan g National Yang-Ming University, School of Medicine, Taipei, Taiwan h Division of Cardiology and Cardiovascular Research Center, Taipei Veterans General Hospital, Taipei, Taiwan abstract article info Article history: Received 8 February 2013 Received in revised form 3 July 2013 Accepted 13 July 2013 Available online 7 August 2013 Keywords: Angiotensin II type I receptor Fibroblast Heart failure Histone deacetylases Transforming growth factor-β Background: Histone deacetylases (HDACs), important epigenetic regulatory enzymes, can reduce cardiac hypertrophy and cardiac fibrosis. However, the mechanisms underlying the antifibrotic activity of HDAC inhibitors remain unclear. The purposes of this study were to evaluate the effects of an HDAC inhibitor on systolic heart failure (HF) and investigate the potential mechanisms. Methods: Echocardiographic, histologic, atrial natriuretic peptide (ANP), and Western blot measurements were performed in HF rats (isoproterenol 100 mg/kg, subcutaneous injection) with and without orally administered (100 mg/kg for 7 consecutive days) MPT0E014 (a novel HDAC inhibitor). Western blot, migration and proliferation assays were carried out on primary isolated cardiac fibroblasts with and without MPT0E014 (0.1 and 1 μM) for 24 h. Results: MPT0E014-treated HF rats (n = 6) had better fraction shortening (48 ± 2 vs. 33 ± 4%, p = 0.006) and smaller left ventricular end diastolic diameter (4.6 ± 0.2 vs. 5.6 ± 0.3 mm, p = 0.031) and systolic diameter (2.4 ± 0.2 vs. 3.9 ± 0.3 mm, p = 0.006) than HF (n = 7) rats. MPT0E014-treated HF rats had lower ANP, cardiac fibrosis, and angiotensin II type I receptor (AT1R), transforming growth factor (TGF)-β, and CaMKIIδ protein levels compared to HF rats. MPT0E014 (at 1 μM, but not 0.1 μM) decreased the migration and prolifera- tion of cardiac fibroblasts. MPT0E014 (0.1 and 1 μM) decreased expression of the AT1R and TGF-β. Conclusions: MPT0E014 improved cardiac contractility and attenuated structural remodeling in isoproterenol- induced dilated cardiomyopathy. The direct antifibrotic activity may have contributed to these beneficial effects. © 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Heart failure (HF) is a common cause of hospitalization, and the prevalence and incidence are increasing [1,2]. Histone deacetylases (HDACs), important epigenetic regulatory enzymes with the ability to deacetylate nucleosome histones and non-histone proteins, have significant effects on tumor growth and cardiovascular diseases [3–9]. Previous studies showed that HDAC inhibitors can reduce cardiac hypertrophy in pathological conditions [10–13]. In addition, HDAC inhibitors may attenuate structural remodeling after a myo- cardial infarction [14]. Therefore, HDAC inhibition was proposed as a potential target for treating HF. However, most studies on HDAC inhibition evaluated cardiac hypertrophy and diastolic dysfunction, and knowledge about the effects of HDAC inhibitors on HF with systolic dysfunction is limited. In addition, the mechanisms underly- ing the beneficial cardiac effects of HDAC inhibitors were not fully elucidated. Adverse left ventricular (LV) remodeling with enhanced cardiac fibrosis plays a critical role in the pathophysiology of HF [15,16]. Higher levels of cardiac fibrosis and collagen formation are associated with adverse LV function and a poor prognosis in HF patients [17–19]. HDAC inhibitors can reduce cardiac fibrosis in pathological hearts [12–14]. Therefore, it is possible that HDAC inhibitor may improve heart function through reducing cardiac fibrosis. However, the mechanisms underlying the antifibrotic activity of HDAC inhibitors are not clear. HDAC inhibition can reduce atrial fibrosis independent of angiotensin II [20]. It is not clear whether HDAC inhibition can directly modulate the activity of cardiac fibroblasts to reduce fibrosis. The International Journal of Cardiology 168 (2013) 4178–4183 ⁎ Corresponding author at: Graduate Institute of Clinical Medicine, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan. E-mail address: a9900112@ms15.hinet.net (Y.-J. Chen). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.07.111 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard