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

Acta Pharmacologica Sinica volume 47, pages 315–327 (2026)Cite this article

Abstract

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.

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Fig. 1: BMP1 expression in post-MI myocardium and serum and the effects of BMP1 inhibitor UK383367 on cardiac activity.
Fig. 2: Proteomic analysis and measurements of proinflammatory cytokines in myocardial tissue from myocardial infarction (MI) mice treated with BMP1 inhibitor UK383367.
Fig. 3: Modulation of macrophage polarization by BMP1 and its inhibitor UK383367 in macrophages.
Fig. 4: BMP1 and UK383367 regulate mitochondrial oxidative phosphorylation, oxidative stress, and bioenergetics in LPS-activated macrophages.
Fig. 5: Effects of BMP1 inhibition by UK383367 on mitochondrial biogenesis and oxidative respiration in LPS-stimulated macrophages.
Fig. 6: BMP1 and UK383367 modulate profibrotic activation and collagen biosynthesis in Ang II-stimulated cardiac fibroblasts.

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Acknowledgements

This research was funded by a grant from the Shandong Provincial Natural Science Foundation (ZR2021MH361). The graphical abstract was drawn using FigDraw.

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  1. These authors contributed equally: Cheng-hu Guo, Qian-qian Wang

Authors and Affiliations

  1. State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, 250012, China

    Cheng-hu Guo, Qian-qian Wang, Jia-qi Li, Lin Chen, Mei-ling Chang, Lian-yue Ma, Xiao-ling Liu & Mei Ni

  2. Department of Cardiology, Affiliated Hospital of Qingdao University, Qingdao, 266000, China

    Qian-qian Wang

  3. Department of Ultrasonography, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China

    Wei Ji

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Contributions

CHG and QQW designed the study, performed the experiments, and wrote the main manuscript text. JQL performed the experiments and analyzed the data. WJ contributed to the proteomic profiling. LC and MLC provided critical insights and revisions. LYM conducted the statistical analyses. MN and XLL supervised the project and reviewed the final manuscript. All the authors have read and approved the final version of the manuscript.

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Correspondence to Xiao-ling Liu or Mei Ni.

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Guo, Ch., Wang, Qq., Li, Jq. et al. BMP1 inhibitor UK383367 improves MI-induced cardiac remodeling and fibrosis in mice via ameliorating macrophage polarization and mitochondrial dysfunction. Acta Pharmacol Sin 47, 315–327 (2026). https://doi.org/10.1038/s41401-025-01655-y

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