2. Academic Validation
  3. Histone deacetylase 3 suppresses the expression of SHP-1 via deacetylation of DNMT1 to promote heart failure

Histone deacetylase 3 suppresses the expression of SHP-1 via deacetylation of DNMT1 to promote heart failure

  • Life Sci. 2022 Mar 1;292:119552. doi: 10.1016/j.lfs.2021.119552.
Yi-Yong Wang 1,  Bin Gao 2,  Yong Yang 3,  Shao-Bin Jia 4,  Xue-Ping Ma 4,  Ming-Hao Zhang 5,  Li-Juan Wang 6,  Ai-Qun Ma 7,  Qin-Ning Zhang 8
Affiliations

Affiliations

  • 1 Department of Cardiovascular Medicine, General Hospital of Ningxia Medical University, China; Department of Cardiovascular Internal Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 2 Department of Cardiology, Zhongwei City People Hospital, China.
  • 3 Department of Cardiovascular Internal Medicine, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, China.
  • 4 Department of Cardiovascular Medicine, General Hospital of Ningxia Medical University, China.
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China.
  • 6 Department of Cardiovascular Medicine, The Second People's Hospital of Yinchuan City, China.
  • 7 Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, China; Key Laboratory of Molecular Cardiology, Shaanxi Province, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, China. Electronic address: maaiqun@medmail.com.cn.
  • 8 School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, China.
PMID: 33932446 DOI: 10.1016/j.lfs.2021.119552
Abstract

Aims: Heart failure (HF) is a progressive disease with recurrent hospitalizations and high mortality. However, the mechanisms underlying HF remain unclear. The present study aimed to explore the regulatory mechanism of histone deacetylase 3 (HDAC3) and DNA Methyltransferase 1 (DNMT1)/Src homology domain 2-containing tyrosine phosphatase-1 (SHP-1) axis in HF.

Methods: The HF rat models and hypertrophy cell models were established. The characteristic parameters of the heart were detected by echocardiography. A multichannel physiological signal acquisition system was used to detect the hemodynamic parameters. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of HDAC3, DNMT1, and SHP-1 mRNAs, while Western blot was applied to analyze the expression of proteins. Masson staining was used to analyze the degree of collagen fiber infiltration. TdT-mediated DUTP nick end labeling (TUNEL) staining was performed to analyze the Apoptosis of myocardial tissue cells. Co-immunoprecipitation (co-IP) was conducted to study the interaction between HDAC3 and DNMT1. Flow cytometry was used to analyze the Apoptosis.

Key findings: HDAC3 and DNMT1 were highly expressed in HF rat and hypertrophy cell models. HDAC3 modified DNMT1 through deacetylation to inhibit ubiquitination-mediated degradation, which promoted the expression of DNMT1. DNMT1 inhibited SHP-1 expression via methylation in the promoter region. In summary, HDAC3 modified DNMT1 by deacetylation to suppress SHP-1 expression, which in turn led to the development of cardiomyocyte hypertrophy-induced HF.

Significance: This study provided potential therapeutic targets for HF treatment.

Keywords

Acetylation; DNA methyltransferase 1; Heart failure; Histone deacetylase 3; Methylation; Src homology domain 2-containing tyrosine phosphatase-1.

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