Discoidin Domain Receptor 1 Promotes Myocardial Fibrosis by Suppressing Specificity Protein 1 Ubiquitination and Degradation in Male Spontaneously Hypertensive Rats.

Abstract

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.