Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination
| Autor: | Tong Liu, Yuheng Li, Yan-Zhong Chang, Jinping Song, Hailin Song, Junmeng Zheng, Wenjuan Xing, Jielin Nie, Caizhi Liu, Ruikai Du, Zifan Liu, Weijia Sun, Yinlong Zhao, Guanghan Kan, Zizhong Liu, Wei Liu, Xiaoyan Jin, Yingxian Li, Junjie Pan, Dingsheng Zhao, Youyou Li, Guohui Zhong, Shukuan Ling, Jianwei Li, Xinxin Yuan, Yixin Jia, Xingcheng Gao |
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| Rok vydání: | 2021 |
| Předmět: |
Ubiquitin-Protein Ligases
Dishevelled Proteins Cardiomegaly 030204 cardiovascular system & hematology Histone Deacetylases Muscle hypertrophy Mice 03 medical and health sciences 0302 clinical medicine Ubiquitin Physiology (medical) medicine Animals Humans 030304 developmental biology Heart Failure Mice Knockout Pressure overload 0303 health sciences biology MEF2 Transcription Factors Protein Stability business.industry Ubiquitination medicine.disease Immunohistochemistry Cell biology Ubiquitin ligase Repressor Proteins Disease Models Animal Heart failure Cardiac hypertrophy biology.protein Disease Susceptibility Calcium-Calmodulin-Dependent Protein Kinase Type 2 Cardiology and Cardiovascular Medicine business Biomarkers Protein Binding Signal Transduction |
| Zdroj: | Circulation. 144:694-711 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.121.054827 |
| Popis: | Background: Without adequate treatment, pathological cardiac hypertrophy induced by sustained pressure overload eventually leads to heart failure. WWP1 (WW domain–containing E3 ubiquitin protein ligase 1) is an important regulator of aging-related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload–induced cardiac remodeling and heart failure is yet to be determined. Methods: To examine the correlation of WWP1 with hypertrophy, we analyzed WWP1 expression in patients with heart failure and mice subjected to transverse aortic constriction (TAC) by Western blotting and immunohistochemical staining. TAC surgery was performed on WWP1 knockout mice to assess the role of WWP1 in cardiac hypertrophy, heart function was examined by echocardiography, and related cellular and molecular markers were examined. Mass spectrometry and coimmunoprecipitation assays were conducted to identify the proteins that interacted with WWP1. Pulse-chase assay, ubiquitination assay, reporter gene assay, and an in vivo mouse model via AAV9 (adeno-associated virus serotype 9) were used to explore the mechanisms by which WWP1 regulates cardiac remodeling. AAV9 carrying cardiac troponin T (cTnT) promoter–driven small hairpin RNA targeting WWP1 (AAV9-cTnT-shWWP1) was administered to investigate its rescue role in TAC-induced cardiac dysfunction. Results: The WWP1 level was significantly increased in the hypertrophic hearts from patients with heart failure and mice subjected to TAC. The results of echocardiography and histology demonstrated that WWP1 knockout protected the heart from TAC-induced hypertrophy. There was a direct interaction between WWP1 and DVL2 (disheveled segment polarity protein 2). DVL2 was stabilized by WWP1-mediated K27-linked polyubiquitination. The role of WWP1 in pressure overload–induced cardiac hypertrophy was mediated by the DVL2/CaMKII/HDAC4/MEF2C signaling pathway. Therapeutic targeting WWP1 almost abolished TAC induced heart dysfunction, suggesting WWP1 as a potential target for treating cardiac hypertrophy and failure. Conclusions: We identified WWP1 as a key therapeutic target for pressure overload induced cardiac remodeling. We also found a novel mechanism regulated by WWP1. WWP1 promotes atypical K27-linked ubiquitin multichain assembly on DVL2 and exacerbates cardiac hypertrophy by the DVL2/CaMKII/HDAC4/MEF2C pathway. |
| Databáze: | OpenAIRE |
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