【Literature Review】China Medical University, Cell Discovery — BAF155 Promotes Cardiac Hypertrophy and Fibrosis by Inhibiting WWP2‑Mediated PARP1 Ubiquitination
Release time:
2026-03-16
I. Research Background
BAF155, a subunit of the SWI/SNF chromatin remodeling complex, is well‑established for its roles in development and tumor biology, but its mechanism in cardiovascular diseases remains unknown. This study found that BAF155 expression was significantly upregulated in heart failure patients, mouse models, and Ang II‑treated cardiomyocytes. Using gene knockout/overexpression mouse models combined with proteomics, Co‑IP, and other techniques, the researchers confirmed that BAF155 promotes Ang II‑induced cardiac hypertrophy and fibrosis by inhibiting WWP2‑mediated ubiquitin‑proteasome degradation of PARP1, revealing BAF155 as a potential therapeutic target for cardiac hypertrophy and fibrosis.
II. Experimental Methods
1. Animal Models:
Cardiac‑specific BAF155 knockout mice (BAF155‑cKO), BAF155 overexpression transgenic mice (BAF155‑TG), and WWP2 knockout mice (WWP2‑cKO) were generated. Ang II (1.5 mg/kg/day) infusion for 14 days was used to establish a cardiac hypertrophy and fibrosis model, with corresponding wild‑type mice serving as controls.
2. Core Techniques:
Echocardiography was used to assess cardiac function (EF%, FS%). H&E, WGA, and Masson staining were performed to evaluate cardiac hypertrophy and fibrosis. Quantitative proteomics was employed to screen for differentially expressed proteins. Co‑IP was used to verify protein‑protein interactions. Immunoblotting (IB) detected protein expression, ubiquitination, and PARylation levels. Immunohistochemistry assessed tissue protein expression.
3. Assessment Parameters:
Cardiac function indicators; markers of cardiac hypertrophy, fibrosis, apoptosis, and DNA damage; PARP1 ubiquitination sites; protein‑protein interactions and PARylation modification levels; phenotypic reversal following PARP1 inhibitor intervention.
4. Echocardiography:
Echocardiographic measurements were acquired using a VINNO 6LAB system with an X10‑23L linear array probe (VERMON) at a center frequency of 23 MHz. Cardiac function was assessed on M‑mode images.
III. Experimental Results
In mice treated with Ang II, the authors observed that cardiac‑specific BAF155 knockout mice (BAF155‑cKO) exhibited significantly higher EF% and FS% compared to control mice (BAF155‑cWT), indicating that BAF155 knockout markedly improved Ang II‑induced cardiac dysfunction (Figure 1A). Consistent with these findings, histological staining (H&E, WGA, Masson) showed that BAF155‑cKO mice had reduced cardiac hypertrophy and fibrosis (Figure 1B). Under physiological conditions, BAF155 overexpression mice (BAF155‑TG) showed slightly lower EF% and FS% compared to wild‑type mice (BAF155‑WT); following Ang II treatment, EF% and FS% decreased more significantly in BAF155‑TG mice, indicating exacerbated cardiac dysfunction (Figure 1C). Histological staining confirmed this trend, with BAF155‑TG mice displaying significantly aggravated cardiac hypertrophy and fibrosis after Ang II treatment (Figure 1D). During this period, intervention with a PARP1 inhibitor in Ang II‑treated BAF155‑TG mice resulted in significant recovery of EF% and FS% as measured by echocardiography, improved cardiac function, and downregulation of cardiac hypertrophy, fibrosis, and PARylation levels, validating the regulatory role of the BAF155‑PARP1 pathway in echocardiographic functional parameters. Integrating echocardiographic and auxiliary experimental results from the mouse models, the study confirmed that BAF155 suppresses WWP2‑mediated PARP1 ubiquitination, leading to upregulation of the PARylation pathway, which in turn reduces EF% and FS% and impairs cardiac function. Knockout of BAF155 or inhibition of PARP1 reversed this pathological process (Figure 1E).
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Figure 1
(A) EF% and FS% of BAF155‑cWT and BAF155‑cKO mice (n = 6).
(B) H&E staining, TRITC‑labeled WGA staining, and Masson's trichrome staining of hearts from BAF155‑cWT and BAF155‑cKO mice (n = 6).
(C) EF% and FS% of BAF155‑WT and BAF155‑TG mice (n = 6).
(D) H&E staining, TRITC‑labeled WGA staining, and Masson's trichrome staining of hearts from BAF155‑WT and BAF155‑TG mice (n = 6).
(E) Model illustrating the role of BAF155 in regulating cardiac homeostasis.
Data are presented as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. Two‑way ANOVA with Bonferroni's multiple comparison test.
Research Conclusion
This study is the first to elucidate the mechanism of BAF155 in cardiovascular disease. It demonstrates that BAF155 binds to WWP2, competitively inhibiting WWP2‑mediated ubiquitination and degradation of PARP1 at lysine residues K249 and K418. This leads to PARP1 accumulation and activation of the downstream PARylation pathway, ultimately promoting Ang II‑induced cardiac hypertrophy and fibrosis. The findings reveal the critical role of the BAF155‑WWP2‑PARP1 axis in cardiac pathological remodeling, providing a novel molecular target (BAF155) for the treatment of pre‑heart failure conditions such as cardiac hypertrophy and fibrosis, while also offering experimental support for the application of PARP1 inhibitors in cardiovascular disease. Future studies may explore the development of specific inhibitors targeting BAF155, or combinatorial strategies modulating the WWP2/PARP1 pathway, to develop new precision therapeutic approaches for cardiovascular disease.
Publication Information
Authors: Naijin Zhang, Ying Zhang, Yong Chen, Hao Qian, Boquan Wu, Saien Lu, Shilong You, Wancheng Xu, Yuanming Zou, Xinyue Huang, Wenbin Wang, Jingwei Liu, Da Li, Liu Cao & Yingxian Sun
Journal: Cell Discovery, volume 9, Article number: 46 (2023)
Original Article Link: https://www.nature.com/articles/s41421-023-00555-x
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