Deletion of ASPP1 in myofibroblasts alleviates myocardial fibrosis by reducing p53 degradation

Shangxuan Li, Meng Yang, Yinfeng Zhao, Yinghe Zhai, Chongsong Sun, Yang Guo, Xiaofang Zhang, Lingmin Zhang, Tao Tian, Ying Yang, Yao Pei, Jialiang Li, Chenhong Li, Lina Xuan, Xingda Li, Deli Zhao, Huike Yang, Yang Zhang (), Baofeng Yang (), Zhiren Zhang (), Zhenwei Pan () and Yanjie Lu ()
Additional contact information
Shangxuan Li: Harbin Medical University
Meng Yang: Harbin Medical University
Yinfeng Zhao: Harbin Medical University
Yinghe Zhai: Harbin Medical University
Chongsong Sun: Harbin Medical University
Yang Guo: Harbin Medical University
Xiaofang Zhang: Harbin Medical University
Lingmin Zhang: Harbin Medical University
Tao Tian: Harbin Medical University
Ying Yang: Harbin Medical University
Yao Pei: Harbin Medical University
Jialiang Li: Harbin Medical University
Chenhong Li: Harbin Medical University
Lina Xuan: Harbin Medical University
Xingda Li: Harbin Medical University
Deli Zhao: The Sixth Affiliated Hospital of Harbin Medical University
Huike Yang: Harbin Medical University
Yang Zhang: Harbin Medical University
Baofeng Yang: Harbin Medical University
Zhiren Zhang: Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment
Zhenwei Pan: Harbin Medical University
Yanjie Lu: Harbin Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract In the healing process of myocardial infarction, cardiac fibroblasts are activated to produce collagen, leading to adverse remodeling and heart failure. Our previous study showed that ASPP1 promotes cardiomyocyte apoptosis by enhancing the nuclear trafficking of p53. We thus explored the influence of ASPP1 on myocardial fibrosis and the underlying mechanisms. Here, we observed that ASPP1 was increased after 4 weeks of MI. Both global and myofibroblast knockout of ASPP1 in mice mitigated cardiac dysfunction and fibrosis after MI. Strikingly, ASPP1 produced the opposite influence on p53 level and cell fate in cardiac fibroblasts and cardiomyocytes. Knockdown of ASPP1 increased p53 levels and inhibited the activity of cardiac fibroblasts. ASPP1 accumulated in the cytoplasm of fibroblasts while the level of p53 was reduced following TGF-β1 stimulation; however, inhibition of ASPP1 increased the p53 level and promoted p53 nuclear translocation. Mechanistically, ASPP1 is directly bound to deubiquitinase OTUB1, thereby promoting the ubiquitination and degradation of p53, attenuating myofibroblast activity and cardiac fibrosis, and improving heart function after MI.

Date: 2024
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DOI: 10.1038/s41467-024-52739-y

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