Deletion of ASPP1 in myofibroblasts alleviates myocardial fibrosis by reducing p53 degradation
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.
Authors
- Shang‐Xuan Li (ORCID: https://orcid.org/0000-0001-9251-7119)
- Zhenwei Pan (ORCID: https://orcid.org/0000-0002-1011-0954)
- Chenhong Li (ORCID: https://orcid.org/0000-0003-3075-1756)
- Lingmin Zhang (ORCID: https://orcid.org/0000-0002-4215-5401)
- Xingda Li (ORCID: https://orcid.org/0000-0001-9737-1251)
- Yanjie Lu (ORCID: https://orcid.org/0000-0002-0283-3167)
- Zhiren Zhang (ORCID: https://orcid.org/0000-0002-5238-2835)
- Lina Xuan (ORCID: https://orcid.org/0000-0003-2127-592X)
- Yang Zhang (ORCID: https://orcid.org/0000-0002-6680-3098)
- Jialiang Li (ORCID: https://orcid.org/0000-0002-9704-4135)
- Tao Tian (ORCID: https://orcid.org/0009-0008-2669-5249)
- Baofeng Yang (ORCID: https://orcid.org/0000-0002-0125-1608)
- Pei Yao (ORCID: https://orcid.org/0000-0003-3998-1996)
- Meng Yang (ORCID: https://orcid.org/0000-0002-4050-644X)
- Deli Zhao (ORCID: https://orcid.org/0000-0001-6193-6361)
- Yinghe Zhai
- Huike Yang (ORCID: https://orcid.org/0000-0003-3876-4914)
- Ying Yang (ORCID: https://orcid.org/0000-0003-4853-6966)
- Yinfeng Zhao
- Yang Guo (ORCID: https://orcid.org/0000-0003-0049-7822)
- Chongsong Sun
- Xiaofang Zhang (ORCID: https://orcid.org/0000-0001-9866-2018)
Institutions
- Harbin Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Third Affiliated Hospital of Harbin Medical University (CN)
- Second Affiliated Hospital of Harbin Medical University (CN)
- First Affiliated Hospital of Harbin Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-28
- DOI
- https://doi.org/10.1038/s41467-024-52739-y
- Citations
- 7
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- National Natural Science Foundation of China