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Published on: June 3, 2018
Discoidin Domain Receptor 1 Promotes Myocardial Fibrosis by Suppressing Specificity Protein 1 Ubiquitination and
Dazhou Lu1,2,3,4,5, Hang Yin1,2,3,4,5, Zerui Wang1,2,3,4,5
1Department of Emergency Medicine Qilu Hospital of Shandong University Jinan China.
Insights
Discoidin domain receptor 1 (DDR1) drives myocardial fibrosis in hypertension. Inhibiting DDR1 improves heart function and reduces fibrosis by stabilizing SP1 and upregulating ROCK1, offering a therapeutic target.
Area of Science:
- Cardiovascular Research
- Fibrosis Mechanisms
- Molecular Biology
Background:
- Myocardial fibrosis (MF) is a key factor in end-stage cardiovascular diseases like hypertension.
- Hypertension-induced fibrotic remodeling contributes to heart failure.
- Discoidin domain receptor 1 (DDR1) is implicated in fibrosis, but its role in hypertension-induced MF is unclear.
Purpose of the Study:
- To investigate the mechanistic role of DDR1 in hypertension-induced myocardial fibrosis.
- To explore DDR1 as a potential therapeutic target for MF.
Main Methods:
- Established a pressure overload-induced MF model in spontaneously hypertensive rats.
- Stimulated cardiac fibroblasts with angiotensin II.
- Assessed cardiac function and fibrosis via echocardiography and histology.
- Utilized molecular biology techniques including Western blotting and PCR.
Main Results:
- DDR1 expression was upregulated in activated cardiac fibroblasts and fibrotic rat hearts.
- DDR1 inhibition improved cardiac structure/function and reduced MF.
- DDR1 interacts with SP1, preventing its degradation and strengthening ROCK1 transcription.
Conclusions:
- DDR1 is a critical mediator of MF progression in hypertension.
- DDR1 inhibition presents a promising therapeutic strategy for MF.
- This study provides a foundation for DDR1-targeted therapies for MF.
Background:
Myocardial fibrosis (MF) is a common pathological manifestation of end-stage cardiovascular diseases such as hypertension. Hypertension increases cardiac afterload and induces fibrotic myocardial remodeling, ultimately progressing to heart failure. DDR1 (discoidin domain receptor 1), a collagen-activated receptor, plays a pivotal role in multiorgan fibrosis progression. However, its specific mechanistic role in hypertension-induced MF remains to be investigated.
Methods:
A pressure overload-induced MF model was established in male spontaneously hypertensive rats, and cardiac fibroblasts were stimulated with angiotensin II to induce a fibrotic phenotype. Cardiac function and fibrosis were assessed through echocardiography combined with histological/cellular staining. Western blotting, quantitative reverse transcription polymerase chain reaction, immunoprecipitation, and ubiquitination assays were used to investigate molecular mechanisms.
Results:
Results demonstrated upregulated DDR1 expression in both activated cardiac fibroblasts and fibrotic hearts of spontaneously hypertensive rats. DDR1 inhibition improved cardiac structure and function in spontaneously hypertensive rats, while reducing the fibrotic phenotype of cardiac fibroblasts and attenuating MF progression. Mechanistically, DDR1 enhances direct interaction with SP1 (specificity protein 1), suppressing its ubiquitination and degradation. SP1 binds to the ROCK1 (rho-associated protein kinase 1) gene promoter to strengthen transcriptional regulation, thereby upregulating ROCK1 and downstream profibrotic signaling pathways.
Conclusions:
In summary, this study demonstrates that DDR1 is a pivotal driver of MF progression, establishing both a theoretical foundation and an experimental basis for DDR1-targeted therapy in MF.
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