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Huangqi-Danshen Decoction Alleviates Cardiac Fibrosis Following Myocardial Infarction by Inhibiting USP22 to Enhance
Jiaqi Hao1, Mengkai Lu2, Muxin Zhang2
1Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
Insights
Huangqi-Danshen decoction (HDD) treats myocardial fibrosis post-heart attack by targeting the USP22-BRD4 epigenetic axis. This promotes BRD4 degradation, reducing fibrosis and improving cardiac function.
Area of Science:
- Cardiology
- Epigenetics
- Pharmacology
Background:
- Myocardial fibrosis is a key factor in heart failure after myocardial infarction (MI).
- Huangqi-Danshen decoction (HDD) shows clinical cardioprotective effects, but its antifibrotic mechanisms are unclear.
Purpose of the Study:
- To investigate HDD's therapeutic effects on myocardial fibrosis post-MI.
- To elucidate the molecular mechanisms underlying HDD's antifibrotic actions.
Main Methods:
- Established a mouse model of myocardial infarction (MI).
- Evaluated cardiac function and fibrosis using echocardiography and histology.
- Utilized proteomic screening and molecular biology in vitro and in vivo.
Main Results:
- HDD improved cardiac function and reduced fibrosis in MI mice.
- Identified BRD4 as a target; HDD decreased BRD4 expression and H3K27ac levels.
- Demonstrated HDD promotes BRD4 degradation via the USP22-BRD4 axis, inhibiting profibrotic gene expression.
Conclusions:
- HDD ameliorates myocardial fibrosis by targeting the USP22-BRD4 axis.
- Promotes BRD4 degradation and inhibits H3K27ac-mediated profibrotic transcription.
- Offers a novel epigenetic therapeutic strategy for post-MI fibrosis.
Background:
Myocardial fibrosis is a critical pathological process in the development of heart failure following myocardial infarction (MI). The Huangqi-Danshen decoction (HDD) has shown cardioprotective effects in clinical practice. Nonetheless, the precise molecular mechanisms underlying its antifibrotic effects remain to be elucidated.
Objective:
This study aimed to systematically investigate the therapeutic effects of HDD on myocardial fibrosis post-MI and to determine the underlying molecular mechanisms.
Methods:
An MI model was established in mice by ligating the left anterior descending coronary artery. Cardiac function and morphology were evaluated using echocardiography and histological analysis. In in vitro experiments, TGF-β1-stimulated human cardiac fibroblasts were treated with HDD-containing serum. The underlying mechanism of HDD was investigated using proteomic screening and molecular biology techniques.
Results:
HDD markedly improved cardiac function and attenuated myocardial fibrosis in MI mice. Proteomic analysis identified BRD4 as a key epigenetic target of HDD. HDD reduced BRD4 expression and H3K27ac levels, accompanied by decreased fibrosis-related marker expression. BRD4 overexpression or TSA treatment counteracted the inhibitory effects of HDD on H3K27ac and fibrotic markers, supporting the involvement of the BRD4/H3K27ac axis. Mechanistically, HDD promoted ubiquitin-proteasome-dependent BRD4 degradation by disrupting the interaction between BRD4 and the deubiquitinase USP22. USP22 overexpression reversed, whereas USP22 knockdown largely phenocopied, the antifibrotic effects of HDD.
Conclusion:
HDD ameliorates myocardial fibrosis by targeting the USP22-BRD4 axis, promoting BRD4 degradation and inhibiting H3K27ac-mediated profibrotic transcription, offering a novel epigenetic therapeutic strategy.
