BMP1 inhibitor UK383367 improves MI-induced cardiac remodeling and fibrosis in mice via ameliorating macrophage polarization and mitochondrial dysfunction.

Despite optimized guideline-directed medical therapy, patients with myocardial infarction (MI) often develop heart failure (HF) primarily because of excessive fibrosis. Bone morphogenetic protein 1 (BMP1) plays a critical role in the fibrotic process, yet its specific role in post-MI myocardial fibrosis remains unclear. In this study, we investigated the complex dynamics between BMP1 and fibrotic processes, offering critical insights for novel strategies to mitigate pathological fibrosis in cardiovascular diseases. An experimental MI model was established in mice by ligating the left anterior descending (LAD) coronary artery. We found that the expression levels of BMP1 were significantly elevated in both the serum of MI patients and the cardiac tissues of MI mice. Administration of the BMP1 inhibitor UK383367 (2 mg/kg, i.p., t.i.d., starting the day of myocardial infarction modeling and maintained for 7 days) in MI mice markedly improved cardiac function, reduced myocardial fibrosis, and attenuated the expression of proinflammatory cytokines, including TNF-α, IL-6 and MCP-1. Proteomic profiling revealed that BMP1 was associated with inflammation and oxidative phosphorylation pathways after MI. We demonstrated that UK383367 (250, 500, and 1000 nM) dose-dependently attenuated M1 macrophage polarization, protected mitochondrial function in lipopolysaccharide-stimulated primary macrophages, and inhibited collagen synthesis in Ang II-stimulated cardiac fibroblasts. Overall, these results reveal a pivotal yet detrimental role for BMP1 in driving myocardial fibrosis and amplifying inflammatory cascades after MI. This study highlights the therapeutic potential of the BMP1 inhibitor UK383367 as a promising alternative to conventional antifibrotic strategies, potentially curbing the progression toward HF.