A novel histone deacetylase inhibitor Se-SAHA attenuates isoproterenol-induced heart failure via antioxidative stress and autophagy inhibition

Tianwei Cheng; Chang Liu; Yufei Wang; Guangru Li; Lifeng Feng; Shengzheng Zhang; Bing Qi; Jianlin Cui; Lihong Guo; Lei Cao; Yanming Wang; Zhi Qi; Liang Yang

doi:10.1016/j.taap.2024.116957

A novel histone deacetylase inhibitor Se-SAHA attenuates isoproterenol-induced heart failure via antioxidative stress and autophagy inhibition

Toxicol Appl Pharmacol. 2024 May 10:487:116957. doi: 10.1016/j.taap.2024.116957. Online ahead of print.

Authors

Tianwei Cheng¹, Chang Liu¹, Yufei Wang¹, Guangru Li¹, Lifeng Feng¹, Shengzheng Zhang¹, Bing Qi¹, Jianlin Cui¹, Lihong Guo², Lei Cao³, Yanming Wang⁴, Zhi Qi⁵, Liang Yang⁶

Affiliations

¹ Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin 300071, China.
² Institute of Digestive Disease, Shengli Oilfield Central Hospital, Dongying 257000, China.
³ Department of General Surgery, Tianjin Union Medical Center, Tianjin 300122, China.
⁴ College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China. Electronic address: wangyanming@nankai.edu.cn.
⁵ Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin 300071, China; Institute of Digestive Disease, Shengli Oilfield Central Hospital, Dongying 257000, China; Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin 300122, China. Electronic address: qizhi@nankai.edu.cn.
⁶ Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin 300071, China; Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin 300122, China. Electronic address: yangliang@nankai.edu.cn.

PMID: 38735590
DOI: 10.1016/j.taap.2024.116957

Abstract

Heart failure is associated with histone deacetylase (HDAC) regulation of gene expression, the inhibition of which is thought to be beneficial for heart failure therapy. Here, we explored the cardioprotective effects and underlying mechanism of a novel selenium-containing HDAC inhibitor, Se-SAHA, on isoproterenol (ISO)-induced heart failure. We found that pretreatment with Se-SAHA attenuated ISO-induced cardiac hypertrophy and fibrosis in neonatal rat ventricular myocytes (NRVMs). Se-SAHA significantly attenuated the generation of ISO-induced reactive oxygen species (ROS) and restored the expression levels of superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) in vitro. Furthermore, Se-SAHA pretreatment prevented the accumulation of autophagosomes. Se-SAHA reversed the high expression of HDAC1 and HDAC6 induced by ISO incubation. However, after the addition of the HDAC agonist, the effect of Se-SAHA on blocking autophagy was inhibited. Using ISO-induced mouse models, cardiac ventricular contractile dysfunction, hypertrophy, and fibrosis was reduced treated by Se-SAHA. In addition, Se-SAHA inhibited HDAC1 and HDAC6 overexpression in ISO-treated mice. Se-SAHA treatment significantly increased the activity of SOD2 and improved the ability to eliminate free radicals. Se-SAHA hindered the excessive levels of the microtubule-associated protein 1 light chain 3 (LC3)-II and Beclin-1 in heart failure mice. Collectively, our results indicate that Se-SAHA exerts cardio-protection against ISO-induced heart failure via antioxidative stress and autophagy inhibition.

Keywords: Autophagy; Cardiac Hypertrophy and Fibrosis; HDAC; Heart Failure; Oxidative Stress; Selenium Analog of SAHA.