2. Academic Validation
  3. Deletion of ASPP1 in myofibroblasts alleviates myocardial fibrosis by reducing p53 degradation

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

  • Nat Commun. 2024 Sep 28;15(1):8425. doi: 10.1038/s41467-024-52739-y.
Shangxuan Li # 1,  Meng Yang # 1,  Yinfeng Zhao # 1,  Yinghe Zhai 1,  Chongsong Sun 1,  Yang Guo 1,  Xiaofang Zhang 1,  Lingmin Zhang 1,  Tao Tian 1,  Ying Yang 1,  Yao Pei 1,  Jialiang Li 1,  Chenhong Li 1,  Lina Xuan 1,  Xingda Li 1,  Deli Zhao 2,  Huike Yang 3,  Yang Zhang 4,  Baofeng Yang 5 6,  Zhiren Zhang 7,  Zhenwei Pan 8 9 10,  Yanjie Lu 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P.R. China.
  • 2 Department of Medical Imaging, The Sixth Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 3 Department of Anatomy, Harbin Medical University, Harbin, P.R. China.
  • 4 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P.R. China. zhangyang0421@hrbmu.edu.cn.
  • 5 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P.R. China. yangbf@ems.hrbmu.edu.cn.
  • 6 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, Harbin, P. R. China. yangbf@ems.hrbmu.edu.cn.
  • 7 Department of Cardiology, The First Affiliated Hospital of Harbin Medical University (HMU), NHC Key Laboratory of Cell Transplantation, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. zhirenz@hrbmu.edu.cn.
  • 8 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P.R. China. panzw@ems.hrbmu.edu.cn.
  • 9 Key Laboratory of Cell Transplantation, The First Affiliated Hospital, Harbin Medical University, Harbin, P. R. China. panzw@ems.hrbmu.edu.cn.
  • 10 School of Basic Medical Sciences, Harbin Medical University, Harbin, P.R. China. panzw@ems.hrbmu.edu.cn.
  • 11 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Labratoray-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, P.R. China. yjlu@hrbmu.edu.cn.
  • # Contributed equally.
PMID: 39341821 DOI: 10.1038/s41467-024-52739-y
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.

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