2. Academic Validation
  3. GCN5-mediated regulation of pathological cardiac hypertrophy via activation of the TAK1-JNK/p38 signaling pathway

GCN5-mediated regulation of pathological cardiac hypertrophy via activation of the TAK1-JNK/p38 signaling pathway

  • Cell Death Dis. 2022 Apr 30;13(4):421. doi: 10.1038/s41419-022-04881-y.
Jia Li 1 2 3,  Chenghui Yan 3,  Yilong Wang 4,  Can Chen 1 2,  Haibo Yu 3,  Dan Liu 5,  Kai Huang 6 7,  Yaling Han 8 9
Affiliations

Affiliations

  • 1 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China.
  • 4 Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 5 Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China. ljmuer@sina.com.
  • 6 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Huangkai1@hust.edu.cn.
  • 7 Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Huangkai1@hust.edu.cn.
  • 8 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. hanyaling@163.net.
  • 9 Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China. hanyaling@163.net.
PMID: 35490166 DOI: 10.1038/s41419-022-04881-y
Abstract

Pathological cardiac hypertrophy is a process of abnormal remodeling of cardiomyocytes in response to pressure overload or other stress stimuli, resulting in myocardial injury, which is a major risk factor for heart failure, leading to increased morbidity and mortality. General control nonrepressed protein 5 (GCN5)/lysine acetyltransferase 2 A, a member of the Histone Acetyltransferase and lysine acetyltransferase families, regulates a variety of physiological and pathological events. However, the function of GCN5 in pathological cardiac hypertrophy remains unclear. This study aimed to explore the role of GCN5 in the development of pathological cardiac hypertrophy. GCN5 expression was increased in isolated neonatal rat cardiomyocytes (NRCMs) and mouse hearts of a hypertrophic mouse model. GCN5 overexpression aggravated the cardiac hypertrophy triggered by transverse aortic constriction surgery. In contrast, inhibition of GCN5 impairs the development of pathological cardiac hypertrophy. Similar results were obtained upon stimulation of NRCMs (having GCN5 overexpressed or knocked down) with phenylephrine. Mechanistically, our results indicate that GCN5 exacerbates cardiac hypertrophy via excessive activation of the transforming growth factor β-activated kinase 1 (TAK1)-c-Jun N-terminal kinase (JNK)/p38 signaling pathway. Using a TAK1-specific inhibitor in rescue experiments confirmed that the activation of TAK1 is essential for GCN5-mediated cardiac hypertrophy. In summary, the current study elucidated the role of GCN5 in promotion of cardiac hypertrophy, thereby implying it to be a potential target for treatment.

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